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Variability in Response to Drugs

  • Robert Twycross
    Affiliations
    Oxford University (R.T.), Oxford, United Kingdom; Royal Marsden (J.R.), London, United Kingdom; Karol Marcinkowski University of Medical Sciences and Hospice Palium, University Hospital of the Lord's Transfiguration (A.K.-L.), Poznan, Poland; Nottingham University Hospitals (S.C.), Nottingham, United Kingdom; Mylan School of Pharmacy, Duquesne University (M.M.), Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Joy Ross
    Affiliations
    Oxford University (R.T.), Oxford, United Kingdom; Royal Marsden (J.R.), London, United Kingdom; Karol Marcinkowski University of Medical Sciences and Hospice Palium, University Hospital of the Lord's Transfiguration (A.K.-L.), Poznan, Poland; Nottingham University Hospitals (S.C.), Nottingham, United Kingdom; Mylan School of Pharmacy, Duquesne University (M.M.), Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Aleksandra Kotlinska-Lemieszek
    Affiliations
    Oxford University (R.T.), Oxford, United Kingdom; Royal Marsden (J.R.), London, United Kingdom; Karol Marcinkowski University of Medical Sciences and Hospice Palium, University Hospital of the Lord's Transfiguration (A.K.-L.), Poznan, Poland; Nottingham University Hospitals (S.C.), Nottingham, United Kingdom; Mylan School of Pharmacy, Duquesne University (M.M.), Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Sarah Charlesworth
    Affiliations
    Oxford University (R.T.), Oxford, United Kingdom; Royal Marsden (J.R.), London, United Kingdom; Karol Marcinkowski University of Medical Sciences and Hospice Palium, University Hospital of the Lord's Transfiguration (A.K.-L.), Poznan, Poland; Nottingham University Hospitals (S.C.), Nottingham, United Kingdom; Mylan School of Pharmacy, Duquesne University (M.M.), Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Mary Mihalyo
    Affiliations
    Oxford University (R.T.), Oxford, United Kingdom; Royal Marsden (J.R.), London, United Kingdom; Karol Marcinkowski University of Medical Sciences and Hospice Palium, University Hospital of the Lord's Transfiguration (A.K.-L.), Poznan, Poland; Nottingham University Hospitals (S.C.), Nottingham, United Kingdom; Mylan School of Pharmacy, Duquesne University (M.M.), Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Andrew Wilcock
    Correspondence
    Address correspondence to: Andrew Wilcock, DM, FRCP, Hayward House Macmillan Specialist Palliative Care Unit, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, United Kingdom.
    Affiliations
    Oxford University (R.T.), Oxford, United Kingdom; Royal Marsden (J.R.), London, United Kingdom; Karol Marcinkowski University of Medical Sciences and Hospice Palium, University Hospital of the Lord's Transfiguration (A.K.-L.), Poznan, Poland; Nottingham University Hospitals (S.C.), Nottingham, United Kingdom; Mylan School of Pharmacy, Duquesne University (M.M.), Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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Open AccessPublished:October 31, 2014DOI:https://doi.org/10.1016/j.jpainsymman.2014.10.003
      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ( [email protected] ).

      Abbreviations

      ATP
      Adenosine triphosphate
      CNS
      Central nervous system
      EM
      Extensive (rapid) metabolizer
      FDA
      Food and Drug Administration
      GI
      Gastrointestinal
      HIV
      Human immunodeficiency virus
      INR
      International normalized ratio
      NSAID
      Nonsteroidal anti-inflammatory drug
      PI
      Package insert
      PM
      Poor (slow) metabolizer
      PO
      Per os, by mouth
      PPI
      Proton-pump inhibitor
      SSRI
      Selective serotinin re-uptake inhibitor
      TCA
      Tricyclic antidepressant
      UDP
      Uridine diphosphate
      UGT
      UDP-glycosyltransferase
      URM
      Ultra-rapid metabolizer
      UTI
      Urinary tract infection
      There is great inter-individual variability in the way people respond to a drug (Box A). Some of this variability is predictable in the presence of clinical factors known to impact upon the pharmacokinetics and/or pharmacodynamics of a drug. For example, an age-related decrease in overall metabolic capacity of the liver, because of reductions in liver mass, liver enzyme activity and hepatic blood flow, results in the elderly being at a significantly higher risk of toxicity from drugs metabolized in the liver. Similarly, an age-related decline in renal function can reduce the excretion of active drugs and metabolites, e.g., morphine-6-glucuronide and morphine-3-glucuronide, increasing the risk of toxicity from morphine.
      Common factors affecting response to drugs

        Adherence

      • Whether drug regimen adhered to or not

        Genetic variation/polymorphism

      • Sequence variation including single nucleotide polymorphisms, gene deletions, gene duplications resulting in altered protein function, e.g., receptors, enzymes, drug transporters

        Pharmacokinetics

      • Absorption
      • Distribution
      • Metabolism
      • Drug–drug and drug–food interactions
      • Excretion

        Pharmacodynamics

      • Receptor–drug interaction and effect
      • Drug–drug and drug–food interactions
      • Decreased/increased receptor affinity due to concurrent disease state

        Physiological factors

      • Gender
      • Age
      • Ethnicity
      • Hormonal changes
      • Circadian and seasonal factors

        Environmental factors

      • Diet
      • Environmental toxins
      • Alcohol and recreational drugs
      • Smoking

        Potential specific associations/concomitant disease

      • Diabetes mellitus
      • GI microbiology
      • Hypoalbuminemia
      • Liver failure
      • Malabsorption
      • Malnutrition
      • Obesity
      • Renal failure
      Genetic variations also contribute towards differences in drug response. Clinically, these are less predictable, although some may be detected with specific testing. They are particularly important for drugs metabolized by cytochrome P450 (CYP450) with the rate of metabolism either reduced or increased. Examples of how these manifest include:
      • reduced or no response because of
        • the failure to convert a pro-drug to its active form
        • increased metabolism of an active drug to an inactive metabolite
      • increased toxicity because of
        • more rapid conversion to the active form or to a metabolite which is more active than the parent drug
        • failure to metabolize an active drug to inactive metabolite(s).
      Other genetic variations, such as genes coding for receptors or drug transporters also can influence overall response, e.g., the μ-opioid receptor or P-glycoprotein transporter and the response to opioids. Induction or inhibition of CYP450 activity also can result from a drug–drug or drug–food interaction causing similar manifestations to those resulting from genetic variation. Each of these factors is considered in more detail below.

      Variability in response to opioids

      Many factors contribute to the inter-individual variation in response to opioids.
      • Droney J.
      • Riley J.
      • Ross J.R.
      Evolving knowledge of opioid genetics in cancer pain.
      • Branford R.
      • Droney J.
      • Ross J.R.
      Opioid genetics: the key to personalized pain control?.
      • Ross J.R.
      • Riley J.
      • Quigley C.
      • Welsh K.I.
      Clinical pharmacology and pharmacotherapy of opioid switching in cancer patients.
      • Somogyi A.A.
      • Barratt D.T.
      • Coller J.K.
      Pharmacogenetics of opioids.

      μ-Opioid receptor

      This is the key receptor mediating opioid analgesia.
      • Matthes H.
      • Maldonado R.
      • Simonin F.
      • et al.
      Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene.
      Genetic variation in the μ-opioid receptor gene has been associated with variation in opioid response in acute post-operative pain,
      • Chou W.Y.
      • Yang L.C.
      • Lu H.F.
      • et al.
      Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty.
      • Chou W.Y.
      • Wang C.H.
      • Liu P.H.
      • et al.
      Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy.
      • Sia A.T.
      • Lim Y.
      • Lim E.C.
      • et al.
      A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia.
      chronic non-cancer pain,
      • Janicki P.K.
      • Schuler G.
      • Francis D.
      • et al.
      A genetic association study of the functional A118G polymorphism of the human mu-opioid receptor gene in patients with acute and chronic pain.
      • Lotsch J.
      • von Hentig N.
      • Freynhagen R.
      • et al.
      Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers.
      and cancer pain.
      • Campa D.
      • Gioia A.
      • Tomei A.
      • Poli P.
      • Barale R.
      Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief.
      • Klepstad P.
      • Rakvåg T.T.
      • Kaasa S.
      • et al.
      The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease.
      However, meta-analysis of opioid pain studies showed no overall association with pain and only weak associations with morphine dose or undesirable effects.
      • Walter C.
      • Lotsch J.
      Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment.

      P-glycoprotein

      The membrane-bound drug transporter P-glycoprotein influences drug absorption and drug excretion.
      • Schinkel A.H.
      The physiological function of drug-transporting P-glycoproteins.
      • Marzolini C.
      • Paus E.
      • Buclin T.
      • Kim R.B.
      Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance.
      It limits the uptake of compounds from the GI tract, regulates the transfer of various drugs across the blood–brain barrier,
      • Ross J.R.
      • Quigley C.
      Pharmacogenetics and opioids.
      and influences drug excretion by the liver and kidneys. It is encoded by the ATP-binding cassette subfamily B member 1 (ABCB1) gene.
      P-glycoprotein modulation of opioid CNS concentrations varies substantially between opioids, with morphine, fentanyl, and methadone being among those most affected.
      • Dagenais C.
      • Graff C.L.
      • Pollack G.M.
      Variable modulation of opioid brain uptake by P-glycoprotein in mice.
      • Barratt D.T.
      • Coller J.K.
      • Hallinan R.
      • et al.
      ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics.
      In animals, removal of P-glycoprotein activity (“knockout” mice) or inhibition by cyclosporine enhances absorption and increases CNS concentrations of fentanyl and morphine, resulting in prolonged analgesia.
      • Thompson S.J.
      • Koszdin K.
      • Bernards C.M.
      Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein.
      Thus, inhibitors of P-glycoprotein (e.g., clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole [not UK], quinidine [not UK], verapamil) could increase CNS effects of opioids.
      Variation in ABCB1 has been associated with increased pain relief with morphine in cancer pain
      • Campa D.
      • Gioia A.
      • Tomei A.
      • Poli P.
      • Barale R.
      Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief.
      and decreased opioid requirements in mixed chronic pain.
      • Lotsch J.
      • von Hentig N.
      • Freynhagen R.
      • et al.
      Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers.
      Studies have shown conflicting results in relation to opioid-induced nausea and vomiting and other undesirable effects.
      • Ross J.R.
      • Riley J.
      • Taegetmeyer A.B.
      • et al.
      Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects.
      • Zwisler S.T.
      • Enggaard T.P.
      • Noehr-Jensen L.
      • et al.
      The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes.
      • Coulbault L.
      • Beaussier M.
      • Verstuyft C.
      • et al.
      Environmental and genetic factors associated with morphine response in the postoperative period.

      Catechol-O-methyltransferase

      Catechol-O-methyltransferase (COMT) is an enzyme that has a significant impact on the metabolism of several important neurotransmitters: dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). The COMT gene is polymorphic, and <25% of Caucasians have low activity variants.
      One common variant in which the amino acid valine is substituted for methionine results in a 3–4 times decrease in COMT activity. It has been associated with increased pain sensitivity and higher μ-opioid system activation in experimental pain,
      • Kim H.
      • Lee H.
      • Rowan J.
      • Brahim J.
      • Dionne R.A.
      Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans.
      • Zubieta J.K.
      • Heitzeg M.M.
      • Smith Y.R.
      • et al.
      COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor.
      and increased morphine dose requirements in cancer patients.
      • Rakvag T.T.
      • Klepstad P.
      • Baar C.
      • et al.
      The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients.
      Other variants of the COMT gene are associated with increased undesirable opioid effects, e.g., nausea and vomiting.
      • Ross J.R.
      • Riley J.
      • Taegetmeyer A.B.
      • et al.
      Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects.
      • Laugsand E.A.
      • Fladvad T.
      • Skorpen F.
      • et al.
      Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids.
      • Kolesnikov Y.
      • Gabovits B.
      • Levin A.
      • Voiko E.
      • Veske A.
      Combined catechol-O-methyltransferase and mu-opioid receptor gene polymorphisms affect morphine postoperative analgesia and central side effects.

      Hepatic metabolism

      Opioid metabolism takes place primarily in the liver. Opioids are metabolized via two main pathways, cytochrome P450 (CYP450) and UDP-glycosyltransferase (UGT; Table 1). Two phases of metabolism are generally described: phase 1 metabolism (modification reactions) and phase 2 metabolism (conjugation reactions).
      Table 1Major opioid enzyme pathways
      DrugPathway
      ++ for CYP pathways may result in clinically important drug–drug interactions (see Appendix).
      CYP2D6CYP3A4/5CYP2B6UGT
      Alfentanil++
      Buprenorphine+++
      Codeine+++
      Dihydrocodeine++
      Fentanyl++
      Hydrocodone+
      Hydromorphone++
      Methadone+++
      Morphine++
      Oxycodone+++
      Oxymorphone++
      Sufentanil++
      Tapentadol++
      Tramadol++++
      a ++ for CYP pathways may result in clinically important drug–drug interactions (see Appendix).
      The most important phase 1 reaction is oxidation, catalyzed by CYP450. The most important phase 2 reaction is glucuronidation, catalyzed by UGT. Glucuronidation produces molecules that are highly hydrophilic and thus easily excreted by the kidneys.
      • Smith H.S.
      Opioid metabolism.
      Drug–drug interactions can occur as a result of changes in CYP450 or UGT activity, although the latter is less well documented.
      • Baxter K.
      • Preston C.L.
      Stockley's drug interactions.

      Genetic polymorphism in cytochrome P450 (CYP450)

      About 75% of all drugs are metabolized partly or completely by cytochrome P450 (Box B). Thus, variation in activity of the cytochrome P450 system can have a major impact on drug action.
      Cytochrome P450 (CYP450)
      • Wilkinson G.R.
      Drug metabolism and variability among patients in drug response.
      CYP450 is a super-family of numerous enzymic proteins responsible for the oxidative metabolism of many drugs and some endogenous substances (e.g., fatty acids, eicosanoids, steroids, bile acids).
      • The root symbol used in naming the individual enzymes is CYP, followed by:
        • a number designating the enzyme family (18 in humans)
        • a capital letter designating the subfamily (44 in humans)
        • a number designating the individual enzyme.
      CYP450 enzymes exist in virtually all tissues, but their highest concentration is in the liver.
      The enzymes concerned with drug metabolism are mostly CYP1–CYP3; these account for about 70% of the total CYP450 content of the liver.
      The most important enzyme is CYP3A4, followed by CYP2D6 and CYP2C9
      The presence of CYP3A4 in the wall of the GI tract is important; it probably acts in conjunction with P-glycoprotein, and together determine the extent of the intestinal absorption and metabolism of CYP3A4 substrates.
      Some 20–25% of drugs are affected by genetic variants of drug-metabolizing enzymes.
      • Stamer U.M.
      • Zhang L.
      • Stüber F.
      Personalized therapy in pain management: where do we stand?.
      The bulk of the population will manifest a normal distribution in terms of the rate of drug metabolism, with activity ranging from well below-average to well above-average, but generally lumped together as extensive metabolizers (EM).
      • Meyer U.
      Genotype or phenotype: the definition of a pharmacogenetic polymorphism.
      In addition, there are discrete genetic populations of individuals who fall beyond the ends of the spectrum. These are designated poor (PM) and ultra-rapid metabolizers (URM). More recently, intermediate metabolizers have been identified for some enzymes (Table 2).
      • Wilkinson G.R.
      Drug metabolism and variability among patients in drug response.
      Table 2Metabolizer status
      • Sajantila A.
      • Palo J.U.
      • Ojanperä I.
      • Davis C.
      • Budowle B.
      Pharmacogenetics in medico-legal context.
      CategoryDescriptionPossible impact
      Poor (PM) or slowLacks functional enzyme (deletion of gene or non-functional variant)Increased toxicity due to slower drug metabolism (e.g., phenytoin, flecainide) or

      Therapeutic failure due to poor metabolism of a pro-drug to its active form (e.g., codeine) or a parent drug to an active metabolite (e.g., tramadol, tamoxifen)
      IntermediateHas two decreased-function enzymes or one decreased, one non-functionalComparable to slow metabolizer but less marked
      Extensive (EM) or rapidHas at least one fully-functional enzymeThis is the norm
      Ultra-rapid (URM)Increased enzyme activity (duplication of gene or other mutation); relatively rareTherapeutic failure due to faster drug metabolism or

      Increased toxicity due to faster conversion of parent drug to more active metabolite (e.g., tramadol) or pro-drug to active form (e.g., codeine)
      As a general rule, an URM may need a higher dose to obtain a therapeutic effect, and a PM a lower dose to prevent increased undesirable effects (Table 3).
      • Stamer U.M.
      • Zhang L.
      • Stüber F.
      Personalized therapy in pain management: where do we stand?.
      Exceptions are ‘pro-drugs’ where metabolites are mostly responsible for the effect of the drug (see below). The effects of such genetic variations can be further modified by the co-administration of the relevant CYP450 inhibitor or inducer.
      Table 3Genetic polymorphism and PM/URM status
      There is roughly a similar number of URM as PM.
      • Smith H.S.
      Opioid metabolism.
      • Wilkinson G.R.
      Drug metabolism and variability among patients in drug response.
      • Poulsen L.
      • Arendt-Nielsen L.
      • Brøsen K.
      • Sindrup S.H.
      The hypoalgesic effect of tramadol in relation to CYP2D6.
      • Riddick D.
      Drug biotransformation.
      • Williams D.G.
      • Patel A.
      • Howard R.F.
      Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability.
      PathwayA selection of affected drugsPopulation affected
      CYP2C9NSAIDsCaucasians 35%
      PhenytoinAsian/African <1%
      Sulfonylureas (glipizide, tolbutamide)
      Warfarin
      CYP2C19Antidepressants (imipramine, sertraline)Asians 10–35%
      Clopidogrel
      Enzyme conversion produces the main active or a more active metabolite.
      Africans 15%
      DiazepamCaucasians 2–5%
      PPIs
      CYP2D6β-Blockers (metoprolol)
      70% Dose reduction recommended in PM; note also that co-administration with paroxetine (2D6 inhibitor) increases plasma concentrations four times.
      Africans 0–34%
      (debrisoquine hydroxylase)Codeine
      Enzyme conversion produces the main active or a more active metabolite.
      Caucasians 5–10%
      FlecainideAsians ≤1%
      Oxycodone
      SSRIs (some, e.g., paroxetine)
      Tamoxifen
      Enzyme conversion produces the main active or a more active metabolite.
      TCAs (imipramine, nortriptyline)
      TCAs most likely to need a lower dose.
      Tramadol
      Enzyme conversion produces the main active or a more active metabolite.
      a There is roughly a similar number of URM as PM.
      b Enzyme conversion produces the main active or a more active metabolite.
      c 70% Dose reduction recommended in PM; note also that co-administration with paroxetine (2D6 inhibitor) increases plasma concentrations four times.
      d TCAs most likely to need a lower dose.
      Of particular note is codeine, for which most of its analgesic effect results from partial conversion to morphine by O-demethylation catalyzed by CYP2D6.
      • Persson K.
      • Hammarlund-Udenaes M.
      • Mortimer O.
      • Rane A.
      The postoperative pharmacokinetics of codeine.
      • Findlay J.W.A.
      • Jones E.C.
      • Butz R.F.
      • Welch R.M.
      Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics.
      Compared with the general population (EM), a PM produces little or no morphine from codeine, and obtains little or no pain relief. On the other hand, undesirable effects are comparable in both categories.
      • Eckhardt K.
      • Li S.
      • Ammon S.
      • et al.
      Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation.
      • Susce M.T.
      • Murray-Carmichael E.
      • de Leon J.
      Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer.
      At the other extreme, URM produce more morphine; this can lead to life-threatening opioid toxicity, which, rarely, has been fatal in children (following adenoidectomy/tonsillectomy; altered respiratory drive due to obstructive sleep apnea was a probable contributing factor).
      • Gasche Y.
      • Daali Y.
      • Fathi M.
      • et al.
      Codeine intoxication associated with ultrarapid CYP2D6 metabolism.
      • Koren G.
      • Cairns J.
      • Chitayat D.
      • Gaedigk A.
      • Leeder S.J.
      Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother.
      • Kirchheiner J.
      • Schmidt H.
      • Tzvetkov M.
      • et al.
      Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication.
      • Racoosin J.A.
      • Roberson D.W.
      • Pacanowski M.A.
      • Nielsen D.R.
      New evidence about an old drug - risk with codeine after adenotonsillectomy.
      • MHRA
      Codeine: restricted use as an analgesic in children and adolescents after European safety review.
      Genetic variation involving CYP2D6 is also important in relation to tramadol, for which the (+) O-desmethyltramadol metabolite is responsible for the opioid analgesic effect. A PM produces little or none and thus obtains little or no analgesic benefit;
      • Stamer U.M.
      • Musshoff F.
      • Kobilay M.
      • et al.
      Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes.
      conversely, an URM produces higher levels with a potential to cause opioid toxicity.
      • Stamer U.M.
      • Stüber F.
      • Muders T.
      • Musshoff F.
      Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication.
      Polymorphism in CYP3A4/5 may be of less clinical significance when considering opioid response.
      • Pirmohamed M.
      • Park B.K.
      Cytochrome P450 enzyme polymorphisms and adverse drug reactions.
      Nonetheless, CYP3A4 activity varies up to 10 times and could be partly responsible for different dose requirements.
      • Haddad A.
      • Davis M.
      • Lagman R.
      The pharmacological importance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions.
      Opioids potentially affected are fentanyl (and related drugs, alfentanil, sufentanil), methadone, oxycodone and, to a lesser extent, buprenorphine.
      Although genetic variation can result in serious consequences, pharmacogenetic testing is not routine, partly because it is not cost-effective, e.g., the impact of testing in relation to warfarin dosing.
      • Kimmel S.E.
      • French B.
      • Kasner S.E.
      • et al.
      COAG Investigators
      A pharmacogenetic versus a clinical algorithm for warfarin dosing.
      • Pirmohamed M.
      • Burnside G.
      • Eriksson N.
      • et al.
      EU-PACT Group
      A randomized trial of genotype-guided dosing of warfarin.
      Thus, generally, close clinical monitoring is recommended for drugs with a major metabolic enzyme pathway affected by genetic polymorphism (see Table 3 and Appendix). However, in some settings, e.g., oncology, testing has been used to determine if an individual is likely to respond to a specific drug, e.g., cetuximab (colorectal cancer), trastuzumab (breast cancer), and dasatinib (acute lymphoblastic leukemia).

      CYP450 drug–drug interactions

      Pharmacokinetic drug–drug interactions mediated through increased or decreased activity of CYP450 enzymes are common, but the resultant clinical impact is difficult to predict.
      • Wilkinson G.R.
      Drug metabolism and variability among patients in drug response.
      • Aeschlimann J.
      • Tyler L.
      Drug interactions associated with cytochrome P-450 enzymes.
      • Johnson M.D.
      • Newkirk G.
      • White Jr., J.R.
      Clinically significant drug interactions.
      • Samer C.F.
      • Lorenzini K.I.
      • Rollason V.
      • Daali Y.
      • Desmeules J.A.
      Applications of CYP450 testing in the clinical setting.
      Some drugs (inducers) increase the activity of specific CYP450 enzymes and others (inhibitors) decrease enzyme activity (see Table 7).
      When CYP450 inhibitors or inducers are co-administered with drugs that are already affected by genetic polymorphisms, they will either augment or mitigate the clinical effects of the genetic variation.

      Induction

      Onset and offset of enzyme induction is gradual, possibly 2–3 weeks, because:
      • onset depends on drug-induced synthesis of new enzyme
      • offset depends on elimination of the enzyme-inducing drug and the decay of the increased enzyme stores.
      Induction of the rate of drug biotransformation generally leads to a decrease in the parent drug plasma concentration, and thus a decreased effect. However, if the substrate drug is an inactive pro-drug, or metabolism produces a more active metabolite, induction will result in an increased effect and possible toxicity.
      The impact of enzyme induction depends on the relative importance of the induced pathway to the substrate's metabolism, whether active metabolites are present, and on the concentration (dose) of the inducer. Sequential dose adjustments, either up or down, may be necessary to maintain the desired clinical effect of the affected drug.
      • Wilkinson G.R.
      Drug metabolism and variability among patients in drug response.
      Converse dose adjustments may be required if the inducer is discontinued, e.g., methadone toxicity has occurred following discontinuation of carbamazepine, an inducer.
      • Benitez-Rosario M.A.
      • Salinas Martín A.
      • Gómez-Ontañón E.
      • Feria M.
      Methadone-induced respiratory depression after discontinuing carbamazepine administration.
      Some anti-epileptics (e.g., carbamazepine, phenobarbital, phenytoin) and some other drugs (e.g., rifampin, St. John's wort) induce members of the CYP3A subfamily (Table 4). Rifampin is the most potent clinically used inducer of cytochrome CYP3A. Some estrogens are metabolized by CYP3A4/5, and induction by rifampin (or another enzyme inducer) can cause oral contraceptive failure.
      Table 4Examples of drug interactions based on enzyme induction of CYP3A4/5
      SubstrateInducersOutcome
      CarbamazepinePhenytoinMetabolism ↑, effect ↓
      MethadoneCarbamazepine, phenobarbital, phenytoin, rifampin, St. John's wortMetabolism ↑, effect ↓ (possible recurrence of pain ± withdrawal symptoms)
      • Kreek M.J.
      • Garfield J.W.
      • Gutjahr C.L.
      • Giusti L.M.
      Rifampin-induced methadone withdrawal.
      MidazolamCarbamazepine, phenytoinMetabolism ↑, effect ↓
      • Backman J.
      • Olkkola K.T.
      • Ojala M.
      • Laaksovirta H.
      • Neuvonen P.J.
      Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin.
      PhenytoinRifampinMetabolism ↑, half-life halved, effect ↓
      • Kay L.
      • Kampmann J.P.
      • Svendsen T.L.
      • et al.
      Influence of rifampicin and isoniazid on the kinetics of phenytoin.
      Protease inhibitors (for HIV)St. John's wortMetabolism ↑, treatment failure
      • Piscitelli S.C.
      • Burstein A.H.
      • Chaitt D.
      • Alfaro R.M.
      • Falloon J.
      Indinavir concentrations and St. John's wort.
      • Henderson L.
      • Yue Q.Y.
      • Bergquist C.
      • Gerden B.
      • Arlett P.
      St. John's wort (Hypericum perforatum): drug interactions and clinical outcomes.
      • Flexner C.
      Dual protease inhibitor therapy in HIV-infected patients: pharmacologic rationale and clinical benefits.
      Chronic alcohol consumption can induce CYP450 enzymes, mostly CYP2E1 and possibly CYP3A. However, in cirrhosis, overall enzyme activity is reduced.

      Inhibition

      Inhibition of drug biotransformation begins within a few hours of the administration of the inhibitor drug. For most drugs, inhibition leads to an increase in the plasma concentration and effect of the substrate drug, and increased risk of toxicity. However, the converse is true with pro-drugs, e.g., clopidogrel, where the plasma concentration of the active metabolite is reduced, increasing the risk of therapeutic failure. Table 5 gives examples of altered drug effects resulting from enzyme inhibition.
      Table 5Examples of drug interactions based on enzyme inhibition
      SubstrateInhibitorsOutcome
      CodeineQuinidine (not UK)

      (CYP2D6)
      Biotransformation to morphine ↓, analgesic effect ↓
      • Sindrup S.
      • Arendt-Nielsen L.
      • Brøsen K.
      • et al.
      The effect of quinidine on the analgesic effect of codeine.
      ClopidogrelPPIs

      (CYP2C19)
      Biotransformation to active metabolite ↓, antithrombotic effect ↓

      MHRA. Interactions between the use clopidogrel and proton pump inhibitors. Safety warnings and messages for medicines. July 6, 2009. Available at: www.mhra.gov.uk/safetyinformation. Accessed October 16, 2014.

      Society for Cardiovascular Angiography and Interventions. A national study of the effect of individual proton pump inhibitors on cardiovascular outcomes in patients treated with clopidogrel following coronary stenting: The Clopidrogrel Medco Outcomes Study. 2009. Available at: www.scai.org.

      • Juurlink D.N.
      • Gomes T.
      • Ko D.T.
      • et al.
      A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.
      • Ho M.
      • Maddox T.M.
      • Wang L.
      • et al.
      Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.
      DiazepamCimetidine

      (multiple CYP)
      Metabolism ↓, effect ↑
      • Klotz U.
      • Reimann I.
      Delayed clearance of diazepam due to cimetidine.
      Lovastatin (not UK), simvastatinClarithromycin, erythromycin

      (CYP3A4/5)
      Metabolism ↓, risk of undesirable effects ↑ (e.g. raised CK plasma concentration, muscle pain, rhabdomyolysis)
      TheophyllineCiprofloxacin

      (CYP1A2)
      Metabolism ↓ (18–113%), effect ↑
      • Nix D.
      • DeVito J.M.
      • Whitbread M.A.
      • Schentag J.J.
      Effect of multiple dose oral ciprofloxacin on the pharmacokinetics of theophylline and indocyanine green.
      TCAsSSRIs

      (multiple CYP)
      Metabolism ↓ (plasma concentrations ↑ 50–350%), effect ↑
      • Vandel S.
      • Bertschy G.
      • Bonin B.
      • et al.
      Tricyclic antidepressant plasma levels after fluoxetine addition.

      Finley P. Selective serotonin reuptake inhibitors: pharmacologic profiles and potential therapeutic distinctions. Ann Pharmacother 28:1359–1369.

      • Pollock B.
      Recent developments in drug metabolism of relevance to psychiatrists.
      WarfarinFluvoxamine

      (multiple CYP)
      Metabolism ↓ (plasma concentration ↑ 65%), effect ↑
      • Tatro D.
      Fluvoxamine drug interactions.
      The mechanism of enzymatic inhibition is either reversible or irreversible. In reversible inhibition, the inhibitor drug (e.g., azole antifungals) binds to the P450 enzyme and prevents the metabolism of the substrate drug.
      • Monaham B.
      Torsades de Pointes occurring in association with terfenadine.
      • Honig P.
      • Wortham D.C.
      • Zamani K.
      • et al.
      Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences.
      The extent of inhibition of one drug by another depends on their relative affinities for the P450 enzyme, and the respective doses. In irreversible inhibition, the enzyme is destroyed or inactivated by the inhibitor drug or its metabolites (e.g., clarithromycin, erythromycin).

      CYP450 drug–drug interactions in palliative care

      It can be challenging to determine the likelihood of a clinically relevant drug–drug interaction in practice. Many patients receiving palliative care are elderly and have several chronic conditions, resulting in the use of numerous drugs, typically 7–8 (range 1–20).
      • Wilcock A.
      • Thomas J.
      • Frisby J.
      • et al.
      Potential for drug interactions involving cytochrome P450 in patients attending palliative day care centres: a multicentre audit.
      • Kotlinska-Lemieszek A.
      • Paulsen O.
      • Kaasa S.
      • Klepstad P.
      Polypharmacy in patients with advanced cancer and pain: a European cross-sectional study of 2282 patients.
      This polypharmacy increases the likelihood of drug interactions involving CYP450, with possibly 10–20% of patients receiving a combination likely to produce a clinically relevant CYP-mediated interaction (Table 6).
      • Wilcock A.
      • Thomas J.
      • Frisby J.
      • et al.
      Potential for drug interactions involving cytochrome P450 in patients attending palliative day care centres: a multicentre audit.
      • Kotlinska-Lemieszek A.
      • Paulsen O.
      • Kaasa S.
      • Klepstad P.
      Polypharmacy in patients with advanced cancer and pain: a European cross-sectional study of 2282 patients.
      For a longer list of commonly used drugs that are moderate-to-potent enzyme inhibitors or inducers, also see Appendix.
      Table 6Common drug combinations likely to produce clinically important CYP-mediated interactions in palliative care patients
      • Wilcock A.
      • Thomas J.
      • Frisby J.
      • et al.
      Potential for drug interactions involving cytochrome P450 in patients attending palliative day care centres: a multicentre audit.
      • Kotlinska-Lemieszek A.
      • Paulsen O.
      • Kaasa S.
      • Klepstad P.
      Polypharmacy in patients with advanced cancer and pain: a European cross-sectional study of 2282 patients.
      Drug combinationLikely outcome of the interaction
      ↑ = drug effect increased; ↓ = effect decreased.
      Benzodiazepines
      Which are full or part substrates of CYP3A4 (see Appendix).
      + CYP3A4 inhibitor

      e.g., diazepam + itraconazole
      Diazepam ↑
      Benzodiazepines
      Which are full or part substrates of CYP3A4 (see Appendix).
       + CYP3A4 inducer

      e.g., midazolam + carbamazepine
      Midazolam ↓
      Corticosteroids + CYP3A4 inhibitor

      e.g., dexamethasone + clarithromycin
      Dexamethasone ↑
      Corticosteroids + CYP3A4 inducer

      e.g., dexamethasone + phenytoin
      Dexamethasone ↓
      Diazepam + omeprazole
      Inhibitor of CYP2C19 (see Appendix).
      Diazepam ↑
      Opioids
      Which are full or part substrates of CYP3A4 (see Appendix).
       + CYP3A4 inhibitor

      e.g., oxycodone + fluconazole
      Oxycodone ↑
      Opioids
      Which are full or part substrates of CYP3A4 (see Appendix).
       + CYP3A4 inducer

      e.g., fentanyl + carbamazepine
      Fentanyl ↓
      a ↑ = drug effect increased; ↓ = effect decreased.
      b Which are full or part substrates of CYP3A4 (see Appendix).
      c Inhibitor of CYP2C19 (see Appendix).
      In one series, about 50% of the interactions involved corticosteroids, and 25% analgesics.
      • Wilcock A.
      • Thomas J.
      • Frisby J.
      • et al.
      Potential for drug interactions involving cytochrome P450 in patients attending palliative day care centres: a multicentre audit.
      In a second series, the most frequently used inducers or inhibitors of CYP450 (and/or P-glycoprotein, or UGT) were dexamethasone, esomeprazole, omeprazole, fluconazole, ciprofloxacin, carbamazepine, carvedilol and verapamil (also see Appendix).
      • Kotlinska-Lemieszek A.
      • Paulsen O.
      • Kaasa S.
      • Klepstad P.
      Polypharmacy in patients with advanced cancer and pain: a European cross-sectional study of 2282 patients.
      Interactions may be missed, e.g., recurrence of pain may be interpreted as disease progression rather than altered analgesic metabolism. The US FDA has a comprehensive list of drug interactions and their significance.

      Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. Available at: http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm. Accessed July 7, 2014.

      Serotonin toxicity is generally a pharmacodynamic interaction resulting from the combination of two or more serotonergic drugs. However, in some circumstances, a pharmacokinetic interaction may contribute to an increase in serotonergic transmission, e.g., fluoxetine (a CYP2D6 and CYP2C19 inhibitor) and amitriptyline.
      The addition of a CYP450 inhibitor to a drug known to prolong the QT interval may result in increased plasma levels, QT prolongation and risk of torsade de pointes, e.g., itraconazole (a CYP3A4 inhibitor) and methadone.

      CYP450 drug–food interactions

      An important interaction associated with CYP450 inhibition is a food–drug interaction involving grapefruit juice and CYP3A substrates administered PO, including some benzodiazepines (diazepam, midazolam, triazolam [not UK]), some statins (atorvastatin, lovastatin [not UK], simvastatin), buspirone, cyclosporine, felodipine, nifedipine, and saquinavir.
      • Wilkinson G.R.
      Drug metabolism and variability among patients in drug response.
      • Benton R.
      • Honig P.K.
      • Zamani K.
      • Cantilena L.R.
      • Woosley R.L.
      Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram.
      • Maskalyk J.
      Grapefruit juice: potential drug interactions.
      • Dahan A.
      • Altman H.
      Food-drug interaction: grapefruit juice augments drug bioavailability-mechanism, extent and relevance.
      • MHRA
      Statins and cytochrome P450 interactions.
      Grapefruit juice contains several bioflavonoids (naringenin, naringin, kaempferol and quercetin) and furanocoumarins (bergamottin), which non-competitively inhibit oxidation reactions mediated by CYP3A enzymes in the wall of the GI tract.
      • Dahan A.
      • Altman H.
      Food-drug interaction: grapefruit juice augments drug bioavailability-mechanism, extent and relevance.
      • Rouseff R.L.
      Liquid chromatographic determination of naringin and neohesperidin as a detector of grapefruit juice in orange juice.
      • Gibaldi M.
      Drug interactions. Part II.
      The effect is unpredictable because the quantity of these components in grapefruit products varies considerably.
      • Tailor S.
      • Gupta A.K.
      • Walker S.E.
      • Shear N.H.
      Peripheral edema due to nifedipine-itraconazole interaction: a case report.
      • Fukuda K.
      • Guo L.
      • Ohashi N.
      • Yoshikawa M.
      • Yamazoe Y.
      Amounts and variation in grapefruit juice of the main components causing grapefruit-drug interaction.
      The effect is maximal when grapefruit juice is ingested 30–60min before the drug. A single 250mL glass of grapefruit juice can inhibit CYP3A for 24–48h and regular intake continually suppresses GI CYP3A.
      • Wilkinson G.R.
      Drug metabolism and variability among patients in drug response.
      • Dahan A.
      • Altman H.
      Food-drug interaction: grapefruit juice augments drug bioavailability-mechanism, extent and relevance.
      Thus, patients taking drugs metabolized by CYP3A are warned to avoid grapefruit juice, particularly if the drug has a narrow therapeutic index, e.g., cyclosporine. Pomelo, Seville orange and lime juices may also inhibit CYP3A;
      • Savage I.
      Forbidden fruit: interactions between medicines, foods and herbal products.
      • Baxter K.
      Drug interactions and fruit juices.
      apple juice has not been implicated.
      Besides inhibiting CYP3A, naringin (and thus grapefruit juice) inhibits organic anion-transporting polypeptide 1A2 (OATP1A2), a carrier protein in the wall of the GI tract that is responsible for the uptake of several drugs. Orange juice (through its major flavonoid, hesperidin) has a similar effect
      • Bailey D.G.
      • Dresser G.K.
      • Leake B.F.
      • Kim R.B.
      Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice.
      and possibly apple juice.

      Sampson M. New reasons to avoid grapefruit and other juices when taking certain drugs. Report from the 236th National Meeting of the American Chemical Society. Philadelphia, August 19, 2008. Available at: www.eurekalert.org/pub_releases/2008-08/acs-nrt072308.php.

      Drugs that may have their absorption reduced by this inhibition include some β-blockers (atenolol, celiprolol (not USA), cyclosporine, etoposide, fexofenadine, itraconazole, and quinolone antibacterials (ciprofloxacin, levofloxacin).
      • Bailey D.G.
      • Dresser G.K.
      • Leake B.F.
      • Kim R.B.
      Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice.

      Sampson M. New reasons to avoid grapefruit and other juices when taking certain drugs. Report from the 236th National Meeting of the American Chemical Society. Philadelphia, August 19, 2008. Available at: www.eurekalert.org/pub_releases/2008-08/acs-nrt072308.php.

      Case reports of serious adverse events related to grapefruit-drug interactions include:
      • amiodarone → torsade de pointes
      • atorvastatin and simvastatin → rhabdomyolysis.
      Other drugs that may be affected by grapefruit include novel oral anticoagulants (apixaban, rivaroxaban), calcium channel blockers (amlodipine, felodipine, verapamil), CNS drugs (quetiapine, buspirone), cytotoxics (nilotinib, lapatinib), and immunosuppressants (cyclosporine, tacrolimus, sirolimus).
      • Bailey D.G.
      • Dresser G.
      • Arnold J.M.
      Grapefruit-medication interactions: forbidden fruit or avoidable consequences?.
      Interactions are generally drug-specific, not a class effect, and the PI should be referred to for more information.
      There is also concern that ingestion of cranberry juice may also modify drug action, mediated through flavonoids that specifically inhibit CYP2C9. Warfarin is an example of a drug that might be affected by this interaction and, indeed, early reports linked cranberry juice with adverse events associated with warfarin.
      • Grant P.
      Warfarin and cranberry juice: an interaction?.
      • Committee on Safety of Medicines
      Interaction between warfarin and cranberry juice: new advice.
      • MHRA
      Possible interaction between warfarin and cranberry juice.
      • Suvarna R.
      • Pirmohamed M.
      • Henderson L.
      Possible interaction between warfarin and cranberry juice.
      However, recent reports suggest that this interaction is unlikely to occur with the amounts of cranberry juice recommended for prophylaxis against UTIs.
      • O'Mara N.
      Does a cranberry juice-warfarin interaction really exist? Detail document.
      • Aston J.L.
      • Lodolce A.E.
      • Shapiro N.L.
      Interaction between warfarin and cranberry juice.
      • Lilja J.J.
      • Backman J.T.
      • Neuvonen P.J.
      Effects of daily ingestion of cranberry juice on the pharmacokinetics of warfarin, tizanidine, and midazolam–probes of CYP2C9, CYP1A2, and CYP3A4.
      • Li Z.
      • Seeram N.P.
      • Carpenter C.L.
      • et al.
      Cranberry does not affect prothrombin time in male subjects on warfarin.
      Nonetheless, an interaction with warfarin cannot be ruled out, particularly when large volumes of cranberry juice are drunk regularly, or when cranberry products other than juice are taken.
      • O'Mara N.
      Does a cranberry juice-warfarin interaction really exist? Detail document.
      • Aston J.L.
      • Lodolce A.E.
      • Shapiro N.L.
      Interaction between warfarin and cranberry juice.
      • Welch J.
      • Forster K.
      Probable elevation in international normalized ratio from cranberry juice.
      Thus, the INR should be monitored more closely in patients on warfarin if they consume large amounts of cranberry juice or take other cranberry supplements for prophylaxis against UTIs.
      • O'Mara N.
      Does a cranberry juice-warfarin interaction really exist? Detail document.

      Quantifying the effects of CYP450 inhibition and induction

      Quantification of the effects of CYP450 inhibitors and inducers is still evolving. The more important enzymes for drug metabolism have generally accepted “probe” substrates and potent inhibitors and inducers (Table 7), and these are used to determine reliable results, e.g., for new drugs in development. Increasingly, data are becoming available that predict the clinical importance of drug–drug interactions. However, there is still much to be determined and, in palliative care where polypharmacy is the norm, in addition to understanding the pharmacokinetics of any drug used, a general awareness of potential interactions is important (see Appendix).
      Table 7Examples of in vivo probe substrates and potent inhibitors and inducers used for evaluation (all PO)

      Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. Available at: http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm. Accessed July 7, 2014.

      EnzymeSubstrateInhibitorInducers
      CYP1A2CaffeineFluvoxamineTobacco smoking
      Theophylline
      CYP2B6Efavirenz
      CYP2C8RepaglinideGemfibrozilRifampin
      CYP2C9TolbutamideAmiodaroneRifampin
      WarfarinFluconazole
      CYP2C19EsomeprazoleFluvoxamineRifampin
      LansoprazoleOmeprazole
      Omeprazole
      Pantoprazole
      CYP2D6DextromethorphanFluoxetineNone known
      Paroxetine
      Quinidine (not UK)
      CYP3A4MidazolamClarithromycinCarbamazepine
      ItraconazoleRifampin
      Ketoconazole
      Ritonavir

      Appendix. Examples of enzyme or transporter protein substrates, inhibitors and inducers which may result in clinically significant drug interactions
      Not an exhaustive list; limited to drugs most likely to be encountered in palliative care and excludes anticancer, HIV and immunosuppressive drugs (seek specific information).
      • Baxter K.
      • Preston C.L.
      Stockley's drug interactions.
      • Kotlinska-Lemieszek A.
      • Paulsen O.
      • Kaasa S.
      • Klepstad P.
      Polypharmacy in patients with advanced cancer and pain: a European cross-sectional study of 2282 patients.

      Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. Available at: http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm. Accessed July 7, 2014.

      Tabled 1
      Enzyme or transporter proteinSubstratesModerate or potent inhibitorsModerate or potent inducers
      CYP1A2AmitriptylineCimetidine
      Cimetidine is classified as a weak inhibitor of multiple CYP enzymes.
      Phenytoin
      ClomipramineCiprofloxacinRifampin
      DuloxetineFluvoxamineTobacco smoking
      Flecainide
      Imipramine
      Melatonin
      Mirtazapine
      Olanzapine
      Propranolol
      Ramelteon (not UK)
      Theophylline
      Tizanidine
      Trimipramine
      CYP2B6MethadoneRifampin
      CYP2C8LoperamideRifampin
      Pioglitazone
      Repaglinide
      Rosiglitazone (not UK)
      CYP2C9
      Enzyme can also be subject to genetic polymorphism, see Table 3.
      CelecoxibAmiodaroneCarbamazepine
      Chlorpropamide (not UK)FluconazoleRifampin
      Diclofenac
      Flurbiprofen
      Fluvastatin
      Gliclazide (not USA)
      Glimepiride
      Glipizide
      Glyburide
      Ibuprofen
      Irbesartan
      Losartan
      Nateglinide
      Phenytoin
      Tolbutamide
      Torsemide
      Warfarin
      CYP2C19
      Enzyme can also be subject to genetic polymorphism, see Table 3.
      AmitriptylineEsomeprazoleRifampin
      CitalopramFluconazole
      ClomipramineFluoxetine
      ClopidogrelFluvoxamine
      DiazepamOmeprazole
      FluoxetineTiclopidine
      ImipramineVoriconazole
      Lansoprazole
      Omeprazole
      Pantoprazole
      Phenytoin
      Sertraline
      CYP2D6
      Enzyme can also be subject to genetic polymorphism, see Table 3.
      AmitriptylineCimetidine
      Cimetidine is classified as a weak inhibitor of multiple CYP enzymes.
      CarvedilolDuloxetine
      CodeineFluoxetine
      Desipramine (not UK)Paroxetine
      Dextromethorphan
      Dihydrocodeine (not USA)
      Duloxetine
      Flecainide
      Fluoxetine
      Hydrocodone (not UK)
      Imipramine
      Metoprolol
      Mirtazapine
      Nebivolol
      Nortriptyline
      Ondansetron
      Oxycodone
      Paracetamol
      Paroxetine
      Pindolol
      Propranolol
      Risperidone
      Sertraline
      Tamoxifen
      Timolol
      Tolterodine
      Tramadol
      Trazodone
      Trimipramine
      Venlafaxine
      CYP3A4/5
      CYP3A enzyme is also expressed in the GI mucosa resulting in substantial first-pass metabolism of some drugs during absorption.
      There is a large overlap between the substrates, inhibitors and inducers of P-glycoprotein and CYP3A.
      AcetaminophenCimetidine
      Cimetidine is classified as a weak inhibitor of multiple CYP enzymes.
      Carbamazepine
      AlfentanilCiprofloxacinModafinil
      AlprazolamClarithromycinPhenobarbital (and other barbiturates)
      AmiodaroneDiltiazemPhenytoin
      AprepitantErythromycinRifampin
      AtorvastatinFluconazoleSt. John's wort
      Budesonide (PO)Grapefruit juice
      BuprenorphineItraconazole
      CarbamazepineVerapamil
      ClarithromycinVoriconazole
      Clonazepam
      Clorazepate
      Codeine
      Dexamethasone
      Diazepam
      Diltiazem
      Domperidone (not USA)
      Erythromycin
      Estradiol
      Ezopiclone (not UK)
      Felodipine
      Fentanyl
      Haloperidol
      Imipramine
      Itraconazole
      Ketamine
      Loperamide
      Losartan
      Lovastatin (not UK)
      Methadone
      Methylprednisolone
      Midazolam
      Mirtazapine
      Nifedipine
      Omeprazole
      Oxybutynin
      Oxycodone
      Phenytoin
      Quetiapine
      Risperidone
      Sertraline
      Simvastatin
      Tamoxifen
      Tolterodine
      Tolvaptan
      Toremifene
      Tramadol
      Trazodone
      Venlafaxine
      Verapamil
      Voriconazole
      Warfarin
      Zolpidem
      Zopiclone (not USA)
      P-glycoprotein
      There is a large overlap between the substrates, inhibitors and inducers of P-glycoprotein and CYP3A.
      DigoxinAmiodaroneCarbamazepine
      LoperamideCarvedilolDexamethasone
      ClarithromycinPhenytoin
      DiltiazemRifampin
      ErythromycinSt. John's wort
      Felodipine
      Itraconazole
      Verapamil
      a Not an exhaustive list; limited to drugs most likely to be encountered in palliative care and excludes anticancer, HIV and immunosuppressive drugs (seek specific information).
      b Cimetidine is classified as a weak inhibitor of multiple CYP enzymes.
      c Enzyme can also be subject to genetic polymorphism, see Table 3.
      d CYP3A enzyme is also expressed in the GI mucosa resulting in substantial first-pass metabolism of some drugs during absorption.
      e There is a large overlap between the substrates, inhibitors and inducers of P-glycoprotein and CYP3A.

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