Abstract
The use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic factors that can sometimes be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After a usual dose, variations in drug toxicity and inefficacy can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. For opioids, the most studied being morphine, mutations in the ABCB1 gene, coding for P-glycoprotein (P-gp), and in the µ-opioid receptor reduce morphine potency. Cytochrome P450 (CYP) 2D6 mutations influence the analgesic effect of codeine and tramadol, and polymorphism of CYP2C9 is potentially linked to an increase in nonsteroidal anti-inflammatory drug-induced adverse events. Furthermore, drug interactions can mimic genetic deficiency and contribute to the variability in response to analgesics. This review summarizes the available data on the pharmacokinetic and pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes, drug transporters, drug targets and other nonopioid biological systems on central and peripheral analgesics.
Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
Bibliography
- 1 Sadee W, Dai Z: Pharmacogenetics/genomics and personalized medicine. Hum. Mol. Genet.14,207–214 (2005).
- 2 Flores CM, Mogil JS: The pharmacogenetics of analgesia: toward a genetically-based approach to pain management. Pharmacogenomics2,177–194 (2001).
- 3 Higgins CF: ABC transporters: physiology, structure and mechanism – an overview. Res. Microbiol.152,205–210 (2001).•• Comprehensive review of ABC transporters.
- 4 Schwab M, Eichelbaum M, Fromm MF: Genetic polymorphisms of the human MDR1 drug transporter. Annu. Rev. Pharmacol. Toxicol.43,285–307 (2003).
- 5 Wang JS, Newport DJ, Stowe ZN, Donovan JL, Pennell PB, DeVane CL: The emerging importance of transporter proteins in the psychopharmacological treatment of the pregnant patient. Drug Metab. Rev.39,723–746 (2007).
- 6 Hoffmeyer S, Burk O, von Richter O et al.: Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl Acad. Sci. USA97,3473–3478 (2000).
- 7 Marzolini C, Paus E, Buclin T, Kim RB: Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin. Pharmacol. Ther.75,13–33 (2004).• Important data on P-gp polymorphisms.
- 8 Hoffmeyer S, Burk O, von Richter O et al.: Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl Acad. Sci. USA97,3473–3478 (2000).
- 9 Johne A, Kopke K, Gerloff T et al.: Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin. Pharmacol. Ther.72,584–594 (2002).
- 10 Fellay J, Marzolini C, Meaden ER et al.: Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet359,30–36 (2002).
- 11 Kerb R: Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett.234,4–33 (2006).• Recent article on implication of P-gp polymorphisms
- 12 Sakaeda T: MDR1 genotype-related pharmacokinetcs: fact or fiction? Drug. Metab. Pharmacokinet.20,391–414 (2005).
- 13 Oude Elferink RPJ, Zadina J: MDR1 P-glycoprotein transports endogenous opioid peptides. Peptides22,2015–2020 (2001).
- 14 Xie R, Hammarlund-Udenaes M, de Boer AG, de Lange EC: The role of P-glycoprotein in blood–brain barrier transport of morphine: transcortical microdialysis studies in MDR1A (-/-) and mdr1a (+/+) mice. Br. J. Pharmacol.128,563–568 (1999).
- 15 King M, Su W, Chang A, Zuckerman A, Pasternak GW: Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs. Nat. Neurosci.4,268–274 (2001).
- 16 Letrent SP, Pollack GM, Brouwer KR, Brouwer LR: Effect of GF120918, a potent P-glycoprotein inhibitor, on morphine pharmacokinetics and pharmacodynamics in rat. Pharm. Res.15,599–605 (1998).
- 17 Kharasch ED, Hoffer C, Whittington D, Sheffels P: Role of P-glycoprotein absorption and clinical effects of morphine. Clin. Pharmacol. Ther.74,543–554 (2003).
- 18 Skarke C, Jarrar M, Erb K, Schmidt H, Geisslinger G, Lotsch J: Respiratory and miotic effects of morphine in healthy volunteers when P-glycoprotein is blocked by quinidine. Clin. Pharmacol. Ther.74,303–311 (2003).
- 19 Klepstad P, Dale O, Skorpen F, Borchgrevink PC, Kaasa S: Genetic variability and clinical efficacy of morphine. Acta Anaesthesiol. Scand.49,902–908 (2005).• Implication of P-gp polymorphism and morphine.
- 20 Meineke I, Freudenthaler S, Hofmann U et al.: Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. Br. J. Clin. Pharmacol.54,592–603 (2002).
- 21 Coulbault L, Beaussier M, Verstuyft C et al.: Environmental and genetic factors associated with morphine response in the postoperative period. Clin. Pharmacol. Ther.79,316–324 (2006).
- 22 Thompson SJ, Koszdin K, Bernards CM: Opiate induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology92,1392–1399 (2000).
- 23 Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS, DeVane CL: Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of ABCB1A gene knockout mice. Psychopharmacology173,132–138 (2004).
- 24 Kharasch ED, Hoffer C, Whittington D: The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone. Br. J. Clin. Pharmacol.57,600–610 (2003).
- 25 Lötsch J, Skarke C, Wieting J et al.: Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin. Pharmacol. Ther.76,72–89 (2006).
- 26 Crettol S, Déglon JJ, Besson J et al.: ABCB1 and cytochrome P450 genotypes and phenotypes: Influence on methadone plasma levels and response to treatment. Clin. Pharmacol. Ther.80,668–681 (2006).
- 27 Coller JK, Barrat DT, Dahlen K, Loennechen MH, Somogyi AA: ABCB1genetic variability and methadone dosage requirement in opioid-dependent individuals. Clin. Pharmacol. Ther.80,683–690 (2006).
- 28 Crettol S, Déglon JJ, Besson J et al.: No influence of ABCB1 haplotypes on methadone dosage requirement. Clin. Pharmacol Ther.83,668–669 (2008).
- 29 Henthorn TK, Liu Y, Mahapatro M, Ng KY: Active transport of fentanyl by the blood-brain barrier. J. Pharmacol. Exp. Ther.289,1084–1089 (1999).
- 30 Cirella VN, Pantuck CB, Lee YJ, Pantick EJ: Effects of cyclosporine on anesthetic action. Anesth. Analg.66,703–706 (1987).
- 31 Kharasch ED, Hoffer C, Altuntas TG, Whittington D: Quinidine as a probe for the role of P-glycoprotein in the intestinal absorption and clinical effects of fentanyl. J. Clin. Pharmacol.44,224–233 (2004).
- 32 Park HJ, Shinn HK, Ryu SH, Lee HS, Park CS, Kang JH: Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans. Clin. Pharmacol. Ther.81,539–546 (2007).
- 33 Kalvass JC, Maurer TS, Pollack GM: Use of plasma and brain unbound fractions to assess the extent of brain distribution of 34 drugs: comparison of unbound concentration ratios to in vivo P-glycoprotein efflux ratios. Drug Metab. Dispos.35,660–666 (2007).
- 34 Waters CM, Avram MJ, Krejcie TC, Henthorn TK: Uptake of fentanyl in pulmonary endothelium. J. Pharmacol. Exp. Ther.288,157–163 (1999).
- 35 Wandel C, Kim R, Wood M, Wood A: Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology96,913–920 (2002).
- 36 Kalvass JC, Olson ER, Pollack GM: Pharmacokinetics and pharmacodynamics of alfentanil in P-glycoprotein-competent and P-glycoprotein-deficient mice: P-glycoprotein efflux alters alfentanil brain disposition and antinociception. Drug. Metab. Dispos.35,455–459 (2007).
- 37 Callaghan R, Riordan JR: Synthetic and natural opiates interact with P-glycoprotein in multidrug-resistant cells. J. Biol. Chem.268,16059–16064 (1993).
- 38 Desmeules JA, Piguet V, Ehret GB, Dayer P: Pharmacogenetics, pharmacokinetics, and analgesia. In: The Genetics of Pain, Progress in Pain Research and Management. Mogil JS (Ed.). IASP Press, WA, USA, 211–238 (2004).
- 39 Boström E, Simonsson US, Hammarlund-Udenaes M: Oxycodone pharmacokinetics and pharmacodynamics in the rat in the presence of the P-glycoprotein inhibitor PSC833. J. Pharm. Sci.94,1060–1066 (2005).
- 40 Hassan HE, Myers AL, Lee IJ, Coop A, Eddington ND: Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats. J. Pharm. Sci.96,2494–2506 (2007).
- 41 Sadeque AJ, Wandel C, He H, Shah S, Wood AJ: Increased drug delivery to the brain by P-glycoprotein inhibition. Clin. Pharmacol. Ther.68,231–237 (2000).
- 42 Skarke C, Jarrar M, Schmidt H et al.: Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics13,651–660 (2003).
- 43 Slanar O, Nobilis M, Kvetina J, Matouskova O, Idle JR, Perlik F: Pharmacokinetics of tramadol is affected by MDR1 polymorphism C3435T. Eur. J. Clin. Pharmacol.63,419–421 (2007).
- 44 Kanaan M, Daali Y, Dayer P, Desmeules J: Lack of interaction of the NMDA receptor antagonists dextromethorphan and dextrorphan with P-glycoprotein. Curr. Drug Metab.9(2),144–151 (2008).
- 45 Buclin T, Biollaz J, Diézi J: Transports rénaux de médicaments: mécanismes et potentiel d’interactions. Med. Hyg.62,682–692 (2004).
- 46 Awara WM, El-Sisi AE, El-Sayad ME, Goda AE: The potential role of cyclooxygenase-2 inhibitors in the treatment of experimentally-induced mammary tumour: does celecoxib enhance the anti-tumour activity of doxorubicin? Pharmacol. Res.50,487–498 (2004).
- 47 Perloff MD, Störmer E, von Moltke LL, Greenblatt DJ: Rapid assessment of P-glycoprotein inhibition and induction in vitro. Pharm. Res.20,1177–1183 (2003).
- 48 Flescher E, Rotem R, Kwon P, Azare J, Jaspers I, Cohen D: Aspirin enhances multidrug resistance gene 1 expression in human Molt-4 T lymphoma cells. Anticancer Res.20,4441–4444 (2000).
- 49 Lu AY, West SB: Multiplicity of mammalian microsomal cytochromes P-450. Pharmacol. Rev.31,277–295 (1979).
- 50 Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP: Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther.270,414–423 (1994).
- 51 Donato MT, Castell JV: Strategies and molecular probes to investigate the role of cytochrome P450 in drug metabolism: focus on in vitro studies. Clin. Pharmacokinet.42,153–178 (2003).
- 52 Zhou H, Josephy D, Kim D, Guengerich P: Functional characterization of four allelic variants of human cytochrome P450 1A2. Arch. Biochem. Biophys.422,23–30 (2004).
- 53 Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C: Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol. Ther.116,496–526 (2007).•• Extensive recent review on CYP polymorphisms.
- 54 Moody DE, Alburges ME, Parker RJ, Collins JM, Strong JM: The involvement of cytochrome P450 3A4 in the N-demethylation of L-α-acetylmethadol (LAAM), norLAAM, and methadone. Drug. Metab. Dispos.25,1347–1353 (1997).
- 55 Herrlin K, Segerdahl M, Gustafsson LL, Kalso E: Methadone, ciprofloxacin, and adverse drug reactions. Lancet.356,2069–2070 (2000).
- 56 Miners JO, Coulter S, Tukey RH, Veronese ME, Birkett DJ: Cytochromes P450, 1A2, and 2C9 are responsible for the human hepatic O-demethylation of R- and S-naproxen. Biochem. Pharmacol.26,1003–1008 (1996).
- 57 Raucy JL, Lasker JM, Liebler CS, Black M: Acetaminophen activation by human liver cytochromes P4502E1 and P4501A2. Arch. Biochem. Biophys.271,270–283 (1989).
- 58 Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M: Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics8,743–759 (2007).•• Detailed review on CYP2B6 polymorphism.
- 59 Kharasch ED, Hoffer C, Whittington D, Sheffels P: Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and mitotic effects of methadone. Clin. Pharmacol. Ther.76,250–269 (2004).
- 60 Crettol S, Déglon JJ, Besson J et al.: Methadone enantiomer plasma levels, CYP2B6, 2C19, and 2C9 genotypes, and response to treatment. Clin. Pharmacol. Ther.78,593–604 (2005).
- 61 Eap CB, Crettol S, Rougier JS et al.: Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation on CYP2B6 slow metababolizers. Clin. Pharmacol. Ther.81,719–728 (2007).
- 62 Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM: Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes P450 in vitro. Drug Metab. Dispos.31,768–772 (2003).
- 63 Umehara K, Shimokama Y, Miyamoto G: Inhibition of human drug metabolizing cytochrome P450 by buprenorphine. Biol. Pharm. Bull.25,682–685 (2002).
- 64 Subrahmanyam V, Renwick AB, Walters DG et al.: Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in liver microsomes. Drug Metab. Dispos.29,1146–1155 (2001).
- 65 Ramirez J, Innocenti F, Schuetz EG et al.: CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitroN-demethylation of meperidine in human liver microsomes. Drug Metab. Dispos.32,930–936 (2004).
- 66 Bort R, Mace K, Boobis A, Gomez-Lechon MJ, Pfeifer A, Castell J: Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem. Pharmacol.58,787–796 (1999).
- 67 Saussele T, Burk O, Blievernicht JK et al.: Selective induction of human hepatic cytochromes P450 2B6 and 3A4 by metamizole. Clin. Pharmacol. Ther.82,265–274 (2007).
- 68 Kirchheiner J, Brockmöller J: Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin. Pharmacol. Ther.77,1–16 (2005).•• Review on CYP2C9 polymorphisms.
- 69 Lee CR, Goldstein JA, Pieper JA: Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in vitro and human data. Pharmacogenetics12,251–263 (2002).
- 70 Totah RA, Rettie AE: Cytochrome P450 2C8: substrates, inhibitors, pharmacogenetics and clinical relevance. Clin. Pharmacol. Ther.77,341–352 (2005).•• Review on CYP2C8 polymorphisms.
- 71 Yasar U, Lundgren S, Eliasson E et al.: Linkage between the CYP2C8 and CYP2C9 genetic polymorphisms. Biochem. Biophys. Res. Commun.299,25–28 (2002).
- 72 Leemann TD, Transon C, Bonnabry P, Dayer P: A major role for cytochrome P450TB (CYP2C subfamily) in the actions of non-steroidal antiinflammatory drugs. Drugs Exp. Clin. Res.19,189–195 (1993).
- 73 Martinez C, Blanco G, Ladero JM et al. Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br. J. Clin. Pharmacol.141,205–208 (2004).
- 74 Pilotto A, Seripa D, Franceschi M et al.: Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms. Gastroenterology133,465–471 (2007).• Link between nonsteroidal anti-inflammatory drugs (NSAIDs) gastrointestinal bleeding and CYP2C9 polymorphism.
- 75 Martin JH, Begg EJ, Kennedy MA, Roberts R, Barclay ML: Is cytochrome P450 2C9 genotype associated with NSAID gastric ulceration? Br. J. Clin. Pharmacol.51,627–630 (2001).
- 76 Vonkeman HE, van de Laar MA, van der Palen J, Brouwers JR, Vermes I: Allele variants of the cytochrome P450 2C9 genotype in white subjects from The Netherlands with serious gastroduodenal ulcers attributable to the use of NSAIDs. Clin. Ther.28,1670–1676 (2006).
- 77 Dorado P, Berecz R, Norberto MJ, Yasar U, Dahl ML, Llerena A: CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers. Eur. J. Clin. Pharmacol.59,221–225 (2003).
- 78 Brenner SS, Herrlinger C, Dilger K et al.: Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib. Clin. Pharmacokinet.42,283–292 (2003).
- 79 Kirchheiner J, Meineke I, Steinbach N, Meisel C, Roots I, Brockmoller J: Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans. Br. J. Clin. Pharmacol.55,51–61 (2003).
- 80 Aithal GP, Day CP, Leathart JBS, Daly AK: Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced hepatitis. Pharmacogenetics10,511–518 (2000).
- 81 Garcia-Martin E, Martinez C, Tabares B, Frias J, Agundez JAG: Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin. Pharmacol. Ther.76,119–127 (2004).
- 82 Hamman MA, Thompson GA, Hall SD: Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. Biochem. Pharmacol.54,33–41 (1997).
- 83 Kirchheiner J, Meineke I, Freytag G, Meisel C, Roots I, Brockmoller J: Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. Clin. Pharmacol. Ther.72,62–75 (2002).
- 84 Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, Goldstein JA: Differences in flurbiprofen pharmacokinetics between CYP2C9*1/*1, *1/*2 and *1/*3 genotypes. Eur. J. Clin. Pharmacol.58,791–794 (2003).
- 85 Lundblad MS, Ohlsson S, Johansson P, Lafolie P, Eliasson E: Accumulation of celecoxib with a 7-fold higher drug exposure in individuals homozygous for CYP2C9*3. Clin. Pharmacol. Ther.79,287–288 (2006).
- 86 Tang C, Shou M, Mei Q, Rushmore TH, Rodrigues AD: Major role of human liver microsomal cytochrome P450 2C9 in the oxidative metabolism of celecoxib a novel cyclooxygenase II inhibitor. J. Pharmacol. Exp. Ther.293,453–459 (2000).
- 87 Tang C, Shou M, Rushmore TH et al.: In vitro metabolism in celecoxib, cyclooxygenase 2 inhibitor by allelic variant forms of human liver microsomal cytochrome P450 C9: correlation with CYPC9 genotype and in vivo pharmacokinetics. Pharmacogenetics11,223–235 (2001).
- 88 Kirchheiner J, Störmer E, Meisel C, Steinbach N, Roots I, Brockmoller J: Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics13,473–480 (2003).
- 89 Zhao J, Leemann T, Dayer P: In vitro oxidation of oxicam NSAIDS by a human liver cytochrome P450. Life Sci.51,575–581 (1992).
- 90 Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M, Chiba K: CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics10,95–104 (2000).
- 91 Lida I, Miyata A, Arai M et al.: Catalytic roles of CYP2C9 and its variants (CYP2C9*2 and CYP2C9*3) in lornoxicam 5´-hydroxylation. Drug. Metab. Dispos.32,7–9 (2004).
- 92 Guo Y, Zhang Y, Wang Y et al.: Role of CYP2C9 and its variants (CYP2C9*3 and CYP2C9*13) in the metabolism of lornoxicam in human. Drug. Metab. Dispos.33,749–753 (2005).
- 93 Vianne-Jorge R, Perini JA, Rondinelli E, Suarez-Kurtz G: CYP2C9 genotypes and the pharmacokinetics of tenoxicam in Brazilians. Clin. Pharmacol. Ther.76,18–26 (2004).
- 94 Perini JA, Vianne-Jorge R, Brogliato AR, Suarez-Kurtz G: Influence of CYP2C9 genotypes on the pharmacokinetics and pharmacodynamics of piroxicam. Clin. Pharmacol. Ther.78,362–369 (2005).
- 95 Bigler J, Whitton J, Lampe JW, Fosdick L, Bostick RM, Potter JD: CYP2C9 and UGT1A6 genotypes modulate the protective effects of acetylsalicylic acid on colon adenoma risk. Cancer Res.61,3566–3569 (2001).
- 96 Samowitz WS, Wolff RK, Curtin K et al.: Interactions between CYP2C9 and UGT1A6 polymorphisms and nonsteroidal anti-inflammatory drugs in colorectal cancer prevention. Clin. Gastroenterol. Hepatol.4,894–901 (2006).
- 97 van Oijen MGH, Huybers S, Peters WHM et al.: Polymorphisms in genes encoding acetylsalicylic acid metabolizing enzymes are unrelated to upper gastrointestinal health in cardiovascular patients on acetylsalicylic acid. Br. J. Clin. Pharmacol.60,623–628 (2005).
- 98 Levy RH: Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia36(Suppl. 5),S8–S13 (1995).
- 99 Desta Z, Zhao X, Shin JG, Flockhart D: Clinical significance of the cytochrome 450 2C19 genetic polymorphisms. Clin. Pharmacokinet.41,913–958 (2002).•• Review on CYP2C19 polymorphisms.
- 100 Sim SC, Risinger C, Dahl ML et al.: A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin. Pharmacol. Ther.79,103–113 (2006).
- 101 Gerber JG, Rhodes RJ, Gal J: Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality16,36–44 (2004).
- 102 McGinnity DF, Parker AJ, Soars M, Riley RJ: Automated definition of the enzymology of drug oxidation by the major human drug metabolizing cytochrome P450s. Drug Metab. Dispos.28,1327–1334 (2000).
- 103 Chen XP, Tan ZR, Huang SL, Huang Z, Ou-Yang DS, Zhou HH: Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects. Clin. Pharmacol. Ther.73,264–271 (2003).
- 104 Zanger UM, Raimondo S, Eichelbaum M: Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch. Pharmacol.369,23–37 (2004).•• Comprehensive review on CYP2D6 polymorphisms.
- 105 Cascorbi I: Pharmacogenetics of cytochrome 2D6: genetic background and clinical implication. Eur. J. Clin. Investig.33,17–22 (2003).•• Comprehensive review on CYP2D6 polymorphisms.
- 106 Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, Fuselli S:CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet. Genomics17,93–101 (2007).
- 107 Dayer P, Desmeules J, Leemann T, Striberni R: Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P450 dbl/bufI). Biochem. Biophys. Res. Commun.152,411–416 (1988).• First report of the bioactivation of codeine by CYP2D6.
- 108 Yue QY, Hasselstrom J, Svensson JO, Sawe J: Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine. Br. J. Clin. Pharmacol.31,635–642 (1991).
- 109 Chen ZR, Somogyi AA, Reynolds G, Bochner F: Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br. J. Clin. Pharmacol.31,381–390 (1991).
- 110 Desmeules J, Gascon MP, Dayer P, Magistris M: Impact of environmental and genetic factor on codeine analgesia. Eur. J. Clin. Pharmacol.41,23–26 (1991).
- 111 Poulsen L, Brosen K, Arendt-Nielsen L, Gram LF, Elbaek K, Sindrup SH: Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur. J. Clin. Pharmacol.51,289–295 (1996).
- 112 Caraco Y, Sheller J, Wood AJJ: Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J. Pharm. Exp. Ther.278,1165–1174 (1996).
- 113 Caraco Y, Sheller J, Wood AJJ: Impact of ethnic origin and quinidine coadministration on codeine’s disposition and pharmacodynamic effects. J. Pharmacol. Exp. Ther.290,413–422 (1999).
- 114 Lötsch J, Skarke C, Schmidt H et al.: Evidence for morphine-independent central nervous opioid effects after administration of codeine: contribution of other codeine metabolites. Clin. Pharmacol. Ther.79,35–48 (2006).
- 115 Kirchheiner J, Schmidt H, Tzvetkov M et al.: Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J.7,257–265 (2007).
- 116 Dalen P, Frengell C, Dahl ML, Sjoqvist F: Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Ther. Drug Monit.19,543–544 (1997).
- 117 Gasche Y, Daali Y, Fathi M et al.: Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N. Engl. J. Med.351,2827–2831 (2004).• Interesting case report.
- 118 Koren G, Cairns J, Chitayat A, Leeder SJ: Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet368,704 (2006).• Interesting case report.
- 119 Paar WD, Poche S, Gerloff J, Dengler HJ: Polymorphic CYP2D6 mediates O-demethylation of the opioids analgesic tramadol. Eur. J. Clin. Pharmacol.53,235–239 (1997).
- 120 Collart L, Luthy C, Favario-Constantin C, Dayer P: Duality of the analgesic effect of tramadol in humans. Schweiz Med Wochenschr.123,2241–2243 (1993).• First report on the complex analgesic effect of tramadol.
- 121 Poulsen L, Arendt-Nielsen L, Brosen K, Sindrup SH: The hypoalgesic effect of tramadol relation to CYP2D6. Clin. Pharmacol. Ther.60,636–644 (1996).
- 122 Stamer UM, Lehnen K, Hothker F et al.: Impact of CYP2D6 on postoperative tramadol analgesia. Pain105,231–238 (2003).
- 123 Desmeules JA, Piguet V, Collart L, Dayer P: Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br. J. Clin. Pharmacol.41,7–12 (1996).
- 124 Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F: Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin. Pharmacol. Ther.82,41–47 (2007).
- 125 Wang G, Zhang H, He F, Fang X: Effect of the CYP2D6*10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. Eur. J. Clin. Pharmacol.62,927–931 (2006).
- 126 Kirchheiner J, Keulen JT, Bauer S, Roots I, Brockmöller J: Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. J. Clin. Psychopharmacol.28,78–83 (2008).
- 127 Kirkwood LC, Nation RL, Somogyi AA: Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine. Br. J. Clin. Pharmacol.44,549–555 (1997).
- 128 Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA: CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br. J. Clin. Pharmacol.57,287–297 (2004).
- 129 Lalovic B, Kharash E, Hoffer C, Risler L, Liu-Chen LY, Shen DD: Pharmacokinetic and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin. Pharmacol. Ther.79,461–479 (2006).
- 130 Schmidt H, Vormfelde SV, Walchner-Bonjean M et al.: The role of active metabolites in dihydrocodeine effects. Int. J. Clin. Pharmacol. Ther.41,95–106 (2003).
- 131 Wilder-Smith CH, Hufschmid E, Thormann W: The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross-over study with extensive and quinidine-induced poor metabolizers. Br. J. Clin. Pharmacol.45,575–581 (1998).
- 132 Webb JA, Rostmi-Hodjegn A, Abdul-Manap R, Hofmann U, Mikus G, Kamali G: Contribution of dihydrocodeine and dihydromorphine to analgesia following dihydrocodeine administration in a man: a PK–PD modeling analysis. Br. J. Clin. Pharmacol.52,35–43 (2001).
- 133 Otton SV, Schadel M, Cheung SW, Kaplan HL, Busto UE, Sellers EM: CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin. Pharmacol. Ther.54,463–472 (1993).
- 134 Kaplan HL, Busto UE, Baylon GJ et al.: Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J. Pharmacol. Exp. Ther.281,103–108 (1997).
- 135 Maddocks I, Somogyi A, Abbott F, Hayball P, Parker D: Attenuation of morphine-induced delirium in palliative care by substitution with infusion of oxycodone. J. Pain Symptom. Manage.12,182–189 (1996).
- 136 Myers AB, Sullivan JE, Koller DMet al.: Correlation of CYP2D6 genotype with response to oxycodone in orthopedic injury related pain. Clin. Pharmacol. Ther.79,P18 (2005).
- 137 Susce MT, Murray-Carmichael E, de Leon J: Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Prog. Neuropsychopharmacol. Biol. Psychiatry30,1356–1358 (2006).
- 138 de Leon J, Dinsmore L. Wedlund P: Adverse drug reactions to oxycodone and hydrocodone in CYP2D6 ultrarapid metabolizers. J. Clin. Psychopharmacol.23,420–421 (2003).
- 139 Samer C, Daali Y, Rebsamen M, Chiappe A, Desmeules J, Dayer P: Determinant role of CYP2D6 and CYP3A4 pathways on the antinociceptive effects of oxycodone. Clin. Pharmacol. Ther.79,P57 (2006).
- 140 Eap CB, Broly F, Baumann P: Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J. Clin. Psychopharmacol.21,229–234 (2001).
- 141 Uehlinger C, Crettol S, Chassot P et al.: Increased (R)-methadone plasma concentrations by quetiapine in cytochrome P450s and ABCB1 genotyped patients. J. Clin. Psychopharmacol.27,273–278 (2007).
- 142 Pérez de los Cobos J, Siñol N, Trujols J et al.: Association of CYP2D6 ultrarapid metabolizer genotype with deficient patient satisfaction regarding methadone maintenance treatment. Drug Alcohol Depend.89,190–194 (2007).
- 143 Coller JK, Joergensen C, Foster DJ et al.: Lack of influence of CYP2D6 genotype on the clearance of (R)-, (S)- and racemic-methadone. Int. J. Clin. Pharmacol. Ther.45,410–417 (2007).
- 144 Wu D, Otton SV, Sproule BA et al.: Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. Br. J. Clin. Pharmacol.35,30–34 (1993).
- 145 Shiran MR, Chowdry J, Rostami-Hodjegan A et al.: A discordance between cytochrome P450 2D6 genotype and phenotype in patients undergoing methadone maintenance treatment. Br. J. Clin. Pharmacol.56,220–224 (2003).
- 146 Zhu W, Cadet P, Baggerman G, Mantione KJ, Stefano GB: Human white blood cells synthesize morphine: CYP2D6 modulation. J. Immunol.175,7357–7362 (2005).
- 147 Candiotti KA, Yang Z, Curia L et al.: The impact of CYP2D6 genetic polymorphism on postoperative morphine consumption. Abstracts of the 2008 Annual Meeting of the American Academy of Pain Medicine. February 12–16, Orlando, FL, USA, (2008).
- 148 Desmeules JA, Kondo Oestreicher M, Piguet V, Allaz AF, Dayer P: Contribution of cytochrome P4502D6 phenotype to the neuromodulatory effects of dextromethorphan. J. Pharmacol. Exp. Ther.288,607–612 (1999).
- 149 Dayer P, Leemann T, Stirberni R: Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytochrome P450 db1 activity. Clin. Pharmacol. Ther.45,34–40 (1989).
- 150 Carpenter CL, Marks SS, Watson DL, Greenberg DA: Brain dextromethorphan and dextrorphan as calcium channel antagonists. Brain Res.439,372–375 (1988).
- 151 Wong BY, Coulter DA, Choi DW, Prince DA: Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices. Neurosci. Lett.85,261–266 (1988).
- 152 Steinberg GK, Bell TE, Yenari MA: Dose escalation safety and tolerance study of the N-methyl-D-aspartate antagonist dextromethorphan in neurosurgery patients. J. Neurosurg.84,860–866 (1996).
- 153 Desmeules JA, Kondo Oestreicher M, Piguet V, Allaz AF, Dayer P: Contribution of cytochrome P450 2D6 phenotype to the neuromodulatory effects of dextromethorphan. J. Pharm. Exp. Ther.288,607–612 (1999).
- 154 Pope LE, Khalil MH, Berg JE, Stiles M, Yakatan GJ, Sellers EM: Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers. J. Clin. Pharmacol.44,1132–1142 (2004).
- 155 Ehret G, Chabert J, Daali Y et al.: Preemptive analgesia induced by the NMDA receptor antagonist dextromethorphan: a randomized controlled study evaluating the impact of CYP2D6 phenotype on the post-operative analgesic requirement of patient. 11th World Congress on Pain, IASP. August 21–26, Sydney, Australia (2005).
- 156 Dong H, Haining RL, Thummel KE, Rettie AE, Nelson SD: Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen. Drug Metab. Dispos.28,1397–1400 (2000).
- 157 Garnett WR: Clinical implications of drug interactions with coxibs. Pharmacotherapy21,1223–1232 (2001).
- 158 Ueshima Y, Tsutsumi M, Takase S, Matsuda Y, Kawahara H: Acetaminophen metabolism in patients with different cytochrome P-4502E1 genotypes. Alcohol Clin. Exp. Res.20(Suppl. 1),25A–28A (1996).
- 159 Lee SS, Buters JT, Pineau T, Fernandez- Salguero P, Gonzalez FJ: Role of CYP2E1 in the hepatotoxicity of acetaminophen. J. Biol. Chem.271,12063–12067 (1996).
- 160 Ingelman-Sundberg M: Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedebergs Arch. Pharmacol.369,89–104 (2004).
- 161 Daly AK: Significance of the minor cytochrome P450 3A isoforms. Clin. Pharmacokinet.45,13–31 (2006).•• Interesting review on CYP3A minor isoforms.
- 162 Gonzalez FJ, Skoda RC, Kimura S et al.: Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature331,442–446 (1988).
- 163 Schirmer M, Rosenberg A, Klein K et al.: Sex-dependent genetic markers of CYP3A4 expression and activity in human liver microsomes. Pharmacogenomics8,443–453 (2007).
- 164 Lamba JK, Lin YS, Schuetz EG, Thummel KE: Genetic contribution to variable human CYP3A-mediated metabolism. Adv. Drug. Deliv. Rev.54,1271–1294 (2002).
- 165 Williams DG, Patel A, Howard RF: Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. Br. J. Anaesth.89,839–845 (2002).
- 166 Hustert E, Haberl M, Burk O et al.: The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics11,773–779 (2001).• Review on CYP3A5 polymorphisms.
- 167 Pinto AG, Wang YH, Chalasani N et al.: Inhibition of human intestinal wall metabolism by macrolide antibiotics: effect of clarithromycin on cytochrome P450 3A4/5 activity and expression. Clin. Pharmacol. Ther.77,178–188 (2005).
- 168 Tang W, Stearns RA, Wang RW, Chiu SHL, Baillie TA: Roles of human hepatic cytochrome P450s 2C9 and 3A4 in the metabolic activation of diclofenac. Chem. Res. Toxicol.12,192–199 (1999).
- 169 Rodrigues AD, Yang Z, Chen C, Pray D, Kim S, Sinz M: Is celecoxib an inducer of cytochrome P450 3A4 in subjects carrying the CYP2C9*3 allele? Clin. Pharmacol. Ther.80,298–301 (2006).
- 170 Rodrigues AD: Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same? Drug. Metab. Dispos.33,1567–1575 (2005).
- 171 Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT: Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin. Pharmacol. Ther.67,275–282 (2000).
- 172 Samer CF, Piguet V, Dayer P, Desmeules JA: Polymorphisme génétique et interactions médicamenteuses: leur importance dans le traitement de la douleur. Can. J. Anaesth.52,806–821 (2005).
- 173 Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin. Pharmacokinet.41,1153–1193 (2002).
- 174 Ehret GB, Desmeules J, Broers B: Methadone-associated long QT syndrome: improving pharmacotherapy for dependence on illegal opioids and lessons learned for pharmacology. Expert Opin. Drug Saf.6,289–303 (2007).
- 175 Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivisto KT: Pharmacokinetic interactions with rifampicin: clinical relevance. Clin. Pharmacokinet.42,819–850 (2003).
- 176 Kharasch ED, Russel M, Mautz D et al.: The role of cytochrome P4503A4 in alfentanil clearance. Implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology87,36–50 (1997).
- 177 Bartkowski RR, Goldberg ME, Larijani GE, Boerner T: Inhibition of alfentanil metabolism by erythromycin. Clin. Pharmacol. Ther.46,99–102 (1989).
- 178 Palkama VJ, Neuvonen PJ, Olkkola KT: The CYP 3A4 inhibitor itraconazole has no effect on the pharmacokinetics of i.v. fentanyl. Br. J. Anaesth.81,598–600 (1998).
- 179 Olkkola KT, Palkama VJ, Neuvonen PJ: Ritonavir’s role in reducing fentanyl clearance and prolonging its half-life. Anesthesiology3,681–685 (1999).
- 180 Hallberg P, Marten L, Wadelius M: Possible fluconazole-fentanyl interaction – a case report. Eur. J. Clin. Pharmacol.62,491–492 (2006).
- 181 Guitton J, Buronfosse T, Désage M, Lepape A, Brazier JL, Beaune P: Possible involvement of multiple cytochrome P450S in fentanyl and sufentanil metabolism as opposed to alfentanil. Biochem. Pharmacol.53,1613–1619 (1997).
- 182 Tateishi T, Krivoruk Y, Ueng YF, Wood AJ, Guengerich FP, Wood M: Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation. Anesth. Analg.82,167–172 (1996).
- 183 Bartkowski RR, Goldberg ME, Huffnagle S, Epstein RH: Sufentanil disposition. Is it affected by erythromycin administration? Anesthesiology78,260–265 (1993).
- 184 Mackenzie PI, Owens IS, Burchell B et al.: The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics7,255–269 (1997).•• Review on the UGT nomenclature.
- 185 Mano Y, Usui T, Kamimura H: Predominant contribution of UDP-glucuronosyltransferase 2B7 in the glucuronidation of racemic flurbiprofen in the human liver. Drug. Metab. Dispos.35,1182–1187 (2007).
- 186 Tang W: The metabolism of diclofenac – enzymology and toxicology perspectives. Curr. Drug. Metab.4,319–329 (2003).
- 187 Mano Y, Usui T, Kamimura H: Contribution of UDP-glucuronosyltransferases 1A9 and 2B7 to the glucuronidation of indomethacin in the human liver. Eur. J. Clin. Pharmacol.63,289–296 (2007).
- 188 Mano Y, Usui T, Kamimura H: Identification of human UDP-glucuronosyltransferase responsible for the glucuronidation of niflumic acid in human liver. Pharm. Res.23,1502–1508 (2006).
- 189 Nishiyama T, Kobori T, Arai K et al.: Identification of human UDP-glucuronosyltransferase isoform(s) responsible for the C-glucuronidation of phenylbutazone. Arch. Biochem. Biophys.454,72–79 (2006).
- 190 Miners JO, Mackenzie PI: Drug glucuronidation in humans. Pharmacol. Ther.51,347–369 (1991).
- 191 Levesque E, Beaulieu M, Hum DW, Belanger A: Characterization and substrate specificity of UGT2B4 (E458): a UDP-glucuronosyltransferase encoded by a polymorphic gene. Pharmacogenetics9,207–216 (1999).
- 192 Nagar S, Zalatoris JJ, Blanchard RL: Human UGT1A6 pharmacogenetics: identificationof a novel SNP, characterization of allele frequencies and functional analysis of recombinant allozymes in human liver tissues and in cultured cells. Pharmacogenetics14,487–499 (2004).
- 193 Mano Y, Usui T, Kamimura H: In vitro inhibitory effects of nonsteroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 1A1-catalysed estradiol 3β-glucuronidation in human liver microsomes. Biopharm. Drug Dispos.26,35–39 (2005).
- 194 Mano Y, Usui T, Kamimura H: In vitro inhibitory effects of nonsteroidal anti-inflammatory drugs on 4-methlumbelliferone glucurnidation in recombinant human UDP-glucuronosyltransferase 1A9-potent inhibition by niflumic acid. Biopharm. Drug Dispos.27,1–6 (2006).
- 195 Mano Y, Usui T, Kamimura H: Inhibitory potential of nonsteroidal anti-inflammatory drugs on UDP-glucuronosyltransferase 2B7 in human liver microsomes. Eur. J. Clin. Pharmacol.63,211–216 (2007).
- 196 Kuehl GE, Bigler J, Potter JD, Lampe JW: Glucuronidation of the aspirin metabolite salicylic acid by expressed UDP-glucuronosyltransferases and human liver microsomes. Drug Metab. Dispos.34,199–202 (2006).
- 197 Chen Y, Kuehl GE, Bigler J et al.: UGT1A6 polymorphism and salicylic glucuronidation following aspirin. Pharmacogenet. Genomics17,571–579 (2007).
- 198 Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP: Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology132,272–281 (2007).
- 199 Court MH, Duan SX, von Moltke LL et al.: Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP glucuronyltransferase isoforms. J. Pharmacol. Exp. Ther.299,98–106 (2001).
- 200 Kostrubsky SE, Sinclair JF, Strom SC et al.: Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicol. Sci.87,146–155 (2005).
- 201 de Morais SM, Uetrecht JP, Wells PG: Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert’s syndrome. Gastroenterology102,577–586 (1992).
- 202 Esteban A, Perez-Mateo M: Heterogeneity of paracetamol metabolism in Gilbert’s syndrome. Eur. J. Drug. Metab. Pharmacokinet.24,9–13 (1999).
- 203 Ullrich D, Sieg A, Blume R, Bock KW, Schroter W, Bircher J: Normal pathways for glucuronidation, sulphation and oxidation of paracetamol in Gilbert’s syndrome. Eur. J. Clin. Invest.17,237–240 (1987).
- 204 Rauchschwalbe SK, Zuhlsdorf MT, Wensing G, Kuhlmann J: Glucuronidation of acetaminophen is independent of UGT1A1 promotor genotype. Int. J. Clin. Pharmacol. Ther.42,73–77 (2004).
- 205 Tankanitlert J, Morales NP, Howard TA et al.: Effects of combined UDP-glucuronosyltransferase (UGT) 1A1*28 and 1A6*2 on paracetamol pharmacokinetics in β-thalassemia/HbE. Pharmacology79,97–103 (2007).
- 206 Coffman BL, Rios GD, King CD, Tephly TR: Human UGT2B7 catalyzes morphine glucuronidation. Drug. Metab. Dispos.25,1–4 (1997).
- 207 Stone AN, Mackenzie PI, Galetin A, Houston JB, Miners JO: Isoform selectivity and kinetics of morphine 3- and 6-glucuronidation by human UDP-glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7. Drug. Metab. Dispos.31,1086–1089 (2003).
- 208 Paul D, Standifer KM, Inturrisi CE, Pasternak GW: Pharmacological characterization of morphine 6b glucuronide very potent morphine metabolite. J. Pharm. Exp. Ther.251,477–483 (1989).
- 209 Coffman BL, King CD, Rios GR, Tephly TR: The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug. Metab. Dispos.26,73–77 (1998).
- 210 Holthe M, Klepstad P, Zahlsen K et al.: Morphine glucuronide to morphine plasma ratios are unaffected by the UGT2B7H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy. Eur. J. Clin. Pharmacol.58,353–356 (2002).
- 211 Duguay Y, Baar C, Skorpen F, Guillemette C: A novel functional polymorphism in the uridine diphosphateglucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clin. Pharmacol. Ther.75,223–233 (2004).
- 212 Sawyer MB, Innocenti F, Das S et al.: A pharmacogenetic study of uridine diphosphate-glucuronyltransferase 2B7 in patients receiving morphine. Clin. Pharmacol. Ther.73,566–574 (2003).
- 213 Darbari DS, van Schaik RH, Capparelli EV, Rana S, McCarter R, van den Anker J: UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease. Am. J. Hematol.83(3),200–202 (2008).
- 214 Holthe M, Rakvag TN, Klepstad P et al.: Sequence variations in the UDP-glucuronyltransferase 2B7 gene: identification of 10 novel SNPs and analysis of their relevance to morphine glucuronidation in cancer patients. Pharmacogenomics J.3,17–26 (2003).
- 215 Court MH, Krishnaswamy S, Hao Q et al.: Evaluation of 3´-azido-3´-deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: specificity and influence of the UGT2B732 polymorphism. Drug Metab. Dispos.31,1125–1133 (2003).
- 216 Green MD, King CD, Mojarrabi B, Mackenzie PI, Tephly TR: Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP glucuronosyltransferase 1A3. Drug Metab. Dispos.26,507–512 (1998).
- 217 King CD, Green MD, Rios GR et al.: The glucuronidation of exogenous and endogenous compounds by stably expressed rat and human UDP-glucuronosyltransferase 1.1. Arch. Biochem. Biophys.332,92–100 (1996).
- 218 Trapnell CB, Klecker RW, Jamis-Dow C, Collins JM: Glucuronidation of 3´-azido-3´-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. Antimicrob. Agents Chemother.42,1592–1596 (1998).
- 219 McCance-Katz EF, Rainey PM, Jatlow P, Friedland G: Methadone effects on zidovudine disposition (AIDS Clinical Trials Group 262). J. Acquir. Immune. Defic. Syndr. Hum. Retrovirol.18,435–443 (1998).
- 220 Zubieta JK, Heitzeg MM, Smith YR et al.: COMT Val158Met genotype affects µ-opioid neurotransmitter responses to a pain stressor. Science299,1240–1243 (2003).
- 221 Rakvag TT, 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. Pain116,73–78 (2005).•• Study on the COMT polymorphism and response to morphine treatment.
- 222 Berthele A, Platzer S, Jochim B et al.: COMT Val108/158Met genotype affects the µ-opioid receptor system in the human brain: evidence from ligand-binding, G-protein activation and preproenkephalin mRNA expression. Neuroimage28,185–193 (2005).
- 223 Reyes-Gibby CC, Shete S, Rakvag T et al.: Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain130,25–30 (2007).
- 224 Hoehe MR, Kopke K, Wendel B et al.: Sequence variability and candidate gene analysis in complex disease: association of µ-opioid receptor gene variation with substance dependence. Hum. Mol. Genet.22,2895–2908 (2000).
- 225 Crowly JJ, Oslin DW, Patkar AA et al.: A genetic association study of the µ opioid receptor and severe opioid dependence. Psychiatr. Genet.13,169–173 (2003).
- 226 Landau L, Cahana A, Smiley RM, Antonarakis SE, Blouin JL: Genetic variability of µ-opioid receptor an in obstetric population. Anesthesiology100,1030–1033 (2004).
- 227 Lötsch J, Skarke C, Grosch S, Darimont J, Schmidt H, Geisslinger G: The polymorphism A118G of the human µ-opioid receptor gene decreases the pupil constrictory effect of morphine-6- glucuronide but not that of morphine. Pharmacogenetics12,3–9 (2002).
- 228 Skarke C, Darimont J, Schmidt H, Geisslinger G, Lötsch J: Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin. Pharmacol. Ther.73,107–121 (2003).• The polymorphism of OPRM1 linked to the analgesic effect of morphine an experimental pain model.
- 229 Romberg R, Olofsen E, Sarton E, den Hartigh J, Taschner PE, Dahan A: Pharmacokinetic–pharmacodynamic modeling of morphine-6-glucuronide induced analgesia in healthy volunteers: absence of sex differences. Anesthesiology100,120–133 (2004).
- 230 Klepstadt P, Rakvag TT, Kaasa S et al.: The 118 A>G polymorphism in the human µ-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol. Scand.48,1232–1239 (2004).• The polymorphism of OPRM1 linked to the analgesic effect of morphine in pain patients.
- 231 Chou WY, Wang CH, Liu PH, Liu CC, Tseng CC, Jawan B: Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology105,334–337 (2006).
- 232 Chou WY, Yang LC, Lu HF et al.: Association of µ-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol. Scand.50,787–792 (2006).
- 233 Campa D, Gioia A, Tomei A, Poli P, Barale R: Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin. Pharmacol. Ther.83(4),559–566 (2008).
- 234 Ide S, Minami M, Ishihara K, Uhl GR, Sora I, Ikeda K: µ opioid receptor-dependent and independent components in effects of tramadol. Neuropharmacology51,651–658 (2006).
- 235 Caraco Y, Maroz Y, Davidson E: Variability in alfentanil analgesia may be attributed to polymorphism in the µ-opioid receptor. Clin. Pharmacol. Ther.69,P63 (2001).
- 236 Oertel BG, Schmidt R, Schneider A, Geisslinger G, Lötsch J: The µ-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenet. Genomics16,625–636 (2006).
- 237 Rees JL, Birch-Machin M, Flanagan N, Healy E, Phillips S, Todd C: Genetic studies of the human melanocortin-1 receptor. Ann. NY Acad. Sci.885,134–142 (1999).•• Study on the MC1R polymorphisms.
- 238 Schaffer JV, Bolognia JL: The melanocortin-1 receptor: red hair and beyond. Arch. Dermatol.137,1477–1485 (2001).
- 239 Liem EB, Lin CM, Suleman MI et al.: Anesthetic requirement is increased in redheads. Anesthesiology101,279–283 (2004).
- 240 Liem EB, Joiner TV, Tsueda K, Sessler DI: Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology102,509–514 (2005).• The link between redheads, pain and MC1R.
- 241 Mogil JS, Wilson SG, Chesler EJ et al.: The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc. Natl Acad. Sci. USA100,4867–4872 (2003).
- 242 Mogil JS, Ritchie J, Smith SB et al.: Melanocortin-1 receptor gene variants affect pain and µ-opioid analgesia in mice and humans. J. Med. Genet.42,583–587 (2005).
- 243 Lee W, Kim RB: Transporters and renal drug elimination. Annu. Rev. Pharmacol. Toxicol.44,137–166 (2004).
- 244 Uwai Y, Saito H, Inui K: Interaction between methotrexate and nonsteroidal anti-inflammatory drugs in organic anion transporter. Eur. J. Pharmacol.409,31–36 (2000).
- 245 Marzolini C, Tirona RG, Kim RB: Pharmacogenomics of the OATP and OAT families. Pharmacogenomics5,273–282 (2004).•• Comprehensive review on the pharmacogenomics of OATP and OAT
- 246 Uwai Y, Taniguchi R, Motohashi H, Saito H, Okuda M, Inui K: Methotrexateloxoprofen interaction: involvement of human organic anion transporters hOAT1 and hOAT3. Drug Metab. Pharmacokinet.19,369–374 (2004).
- 247 Mulato AS, Ho ES, Cihlar T: Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1. J. Pharmacol. Exp. Ther.295,10–15 (2000).
- 248 El-Sheikh AA, van den Heuvel JJ, Koenderink JB, Russel FG: Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport. J. Pharmacol. Exp. Ther.320,229–235 (2007).
- 249 Xiong H, Turner KC, Ward ES, Jansen PL, Brouwer KL: Altered hepatobiliary disposition of acetaminophen glucuronide in isolated perfused livers from multidrug resistance-associated protein 2-deficient TR(-) rats. J. Pharmacol. Exp. Ther.295,512–518 (2000).
- 250 Hirouchi M, Suzuki H, Itoda M et al.: Characterization of the cellular localization, expression level, and function of SNP variants of MRP2/ABCC2. Pharm. Res.21,742–748 (2004).
- 251 Nagar S, Walther S, Blanchard RL: Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation. Mol. Pharmacol.69,2084–2092 (2006).
- 252 King RS, Ghosh AA, Wu J: Inhibition of human phenol and estrogen sulfotransferase by certain non-steroidal anti-inflammatory agents. Curr. Drug. Metab.7,745–753 (2006).
- 253 Ulrich CM, Bigler J, Sibert J, Greene EA, Sparks R, Carlson CS, Potter JD: Cyclooxygenase 1 (COX1) polymorphisms in African–American and Caucasian populations. Human Mut.20,409–410 (2002).• Article on COX1 polymorphisms.
- 254 Halushka MK, Walker LP, Halushka PV: Genetic variation in cyclooxygenase 1: effects on response to aspirin. Clin. Pharmacol. Ther.73,122–130 (2003).
- 255 Lee CR, Bottone FG Jr, Krahn JM et al.: Identification and functional characterization of polymorphisms in human cyclooxygenase-1 (PTGS1). Pharmacogenet. Genomics.17,145–160 (2007).
- 256 Lee YS, Kim H, Wu TX, Wang XM, Dionne RA: Genetically mediated interindividual variation in analgesic responses to cyclooxygenase inhibitory drugs. Clin. Pharmacol. Ther.79,407–418 (2006).
- 257 Skarke C, Reus M, Schmidt R et al.: The cyclooxygenase 2 genetic variant -765G>C does not modulate the effects of celecoxib on prostaglandin E2 production. Clin. Pharmacol. Ther.80,621–632 (2006).
- 258 Codd EE, Sjamk RP, Schupsky JJ et al.: Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J. Pharmacol. Exp. Ther.274,1263–1270 (1995).
- 259 Small KM, Liggett SB: Identification and functional characterization of α(2)-adrenoreceptor polymorphisms. Trends Pharmacol. Sci.22,471–477 (2001).• Review of α(2)-adrenoreceptor polymorphisms.
- 260 Arcioni R, Della Rocca M, Romano S, Romano R, Pietropaoli P, Gasparetto A: Ondansetron inhibits the analgesic effect of tramadol: a possible 5-HT3 spinal receptor involvement in acute pain in humans. Anesth. Analg.94,1553–1557 (2002).• Important data supporting the polymorphism of serotonin receptors.
- 261 De Witte JL, Schoenmaekers B, Sessler SI, Deloof T: The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron. Anesth. Analg.92,1319–1321 (2001).
- 262 Rojas-Corrales MO, Ortega-Alvaro A, Gibert-Rahola J et al.: Pindolol, a β-adrenoreceptor blocker/5-hydroxytryptamine (1A/1B) antagonist, enhances the analgesic effect of tramadol. Pain88,119–124 (2000).• Important data supporting the polymorphism of serotonin receptors.
- 263 Raffa RB, Friderichs E, Reimann W et al.: Opioid and non opioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J. Pharmacol. Exp. Ther.260,275–285 (1992).
- 264 Oliva P, Aurilio C, Massimo F et al.: The antinociceptive effect of tramadol in the formalin test is mediated by the serotoninergic component. Eur. J. Pharmacol.445,179–185 (2002).
- 265 Ozdogan UK, Lahdesmaki J, Scheinin M: The analgesic efficacy of partial opioid agonists is increased in mice with targeted inactivation of α2A-adrenoreceptor gene. Eur. J. Pharmacol529,105–113 (2006).
- 301 Home page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee www.imm.ki.se/cypalleles