Abstract
Objective
Inhibition of cytochrome P P450 (CYP) enzymes, in particular CYP3A4 and CYP2D6, is an important drug-interacting mechanism. The objective of our study was to assess how frequently CYP3A4 and CYP2D6 inhibitors are co-prescribed with substrates of the respective enzymes.
Methods
Included inhibitors were clarithromycin, erythromycin, fluconazole, itraconazole, ketoconazole and nefazodone (CYP3A4 inhibitors) and bupropion, fluoxetine, paroxetine and terbinafine (CYP2D6 inhibitors). The inhibitors were combined with substrates shown to be pharmacokinetically sensitive towards inhibition (190 drug pairs in total). Lists of patients receiving inhibitors and substrates were drawn from prescription databases (~43,500 patients) of three Norwegian primary pharmacies during a 6-month period (July 2002 to January 2003). The lists were matched on name and date of birth to identify patients using drug pairs. Concurrent use was made probable from dates of purchase and drug profiles.
Results
Inhibitors were prescribed to 2,062 patients. Altogether, 369 events of substrate co-prescription were registered. The highest frequencies of co-prescribed substrates were found for paroxetine (101 events per 267 patients, 38%), fluoxetine (36 events per 110 patients, 33%) and clarithromycin (59 events per 242 patients, 24%). The drugs most often detected in combination with inhibitors were codeine (116 events) and metoprolol (38 events) for CYP2D6 and zopiclone (45 events) and simvastatin (26 events) for CYP3A4.
Conclusion
Several commonly used CYP2D6 and CYP3A4 inhibitors are frequently co-prescribed with substrates in Norwegian clinical practice. Alertness when inhibitors are prescribed would aid physicians and pharmacists to detect many drug combinations with potential interaction risk.
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References
Abdel-Rahman SM, Gotschall RR, Kauffman RE, Leeder JS, Kearns GL (1999) Investigation of terbinafine as a CYP2D6 inhibitor in vivo. Clin Pharmacol Ther 65:465–472
Abernethy DR, Barbey JT, Franc J, Brown KS, Feirrera I, Ford N, Salazar DE (2001) Loratadine and terfenadine interaction with nefazodone: both antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 69:96–103
Alfaro CL, Lam YW, Simpson J, Ereshefsky L (2000) CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: intraindividual variability and plasma concentration correlations. J Clin Pharmacol 40:58–66
Aranko K, Luurila H, Backman JT, Neuvonen PJ, Olkkola KT (1994) The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone. Br J Clin Pharmacol 38:363–367
Avenoso A, Spina E, Campo G, Facciola G, Ferlito M, Zuccaro P, Perucca E, Caputi AP (1997) Interaction between fluoxetine and haloperidol: pharmacokinetic and clinical implications. Pharmacol Res 35:335–339
Backman JT, Olkkola KT, Aranko K, Himberg JJ, Neuvonen PJ (1994) Dose of midazolam should be reduced during diltiazem and verapamil treatments. Br J Clin Pharmacol 37:221–225
Baumann P, Meyer JW, Amey M, Baettig D, Bryois C, Jonzier-Perey M, Koeb L, Monney C, Woggon B (1992) Dextromethorphan and mephenytoin phenotyping of patients treated with thioridazine or amitriptyline. Ther Drug Monit 14:1–8
Bottiger Y, Sawe J, Brattstrom C, Tollemar J, Burke JT, Hass G, Zimmerman JJ (2001) Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers. Clin Pharmacol Ther 69:32–40
Brannan MD, Reidenberg P, Radwanski E, Shneyer L, Lin CC, Cayen MN, Affrime MB (1995) Loratadine administered concomitantly with erythromycin: pharmacokinetic and electrocardiographic evaluations. Clin Pharmacol Ther 58:269–278
Carr RA, Edmonds A, Shi H, Locke CS, Gustavson LE, Craft JC, Harris SI, Palmer R (1998) Steady-state pharmacokinetics and electrocardiographic pharmacodynamics of clarithromycin and loratadine after individual or concomitant administration. Antimicrob Agents Chemother 42:1176–1180
Danielson PB (2002) The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab 3:561–597
Eap CB, Lessard E, Baumann P, Brawand-Amey M, Yessine MA, O’Hara G, Turgeon J (2003) Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans. Pharmacogenetics 13:39–47
el-Yazigi A, Chaleby K, Gad A, Raines DA (1995) Steady-state kinetics of fluoxetine and amitriptyline in patients treated with a combination of these drugs as compared with those treated with amitriptyline alone. J Clin Pharmacol 35:17–21
Fernandes LC, Kilicarslan T, Kaplan HL, Tyndale RF, Sellers EM, Romach MK (2002) Treatment of codeine dependence with inhibitors of cytochrome P450 2D6. J Clin Psychopharmacol 22:326–329
Floren LC, Bekersky I, Benet LZ, Mekki Q, Dressler D, Lee JW, Roberts JP, Hebert MF (1997) Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther 62:41–49
Foradori A, Mezzano S, Videla C, Pefaur J, Elberg A (1998) Modification of the pharmacokinetics of cyclosporine A and metabolites by the concomitant use of Neoral and diltiazem or ketoconazole in stable adult kidney transplants. Transplant Proc 30:1685–1687
Fost DA, Leung DY, Martin RJ, Brown EE, Szefler SJ, Spahn JD (1999) Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy. J Allergy Clin Immunol 103:1031–1035
Glynn AM, Slaughter RL, Brass C, D’Ambrosio R, Jusko WJ (1986) Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion. Clin Pharmacol Ther 39:654–659
Goff DC, Midha KK, Sarid-Segal O, Hubbard JW, Amico E (1995) A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia. Psychopharmacology (Berl) 117:417–423
Greenblatt DJ, von Moltke LL, Harmatz JS, Mertzanis P, Graf JA, Durol AL, Counihan M, Roth-Schechter B, Shader RI (1998) Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin Pharmacol Ther 64:661–671
Greenblatt DJ, Wright CE, von Moltke LL, Harmatz JS, Ehrenberg BL, Harrel LM, Corbett K, Counihan M, Tobias S, Shader RI (1998) Ketoconazole inhibition of triazolam and alprazolam clearance: differential kinetic and dynamic consequences. Clin Pharmacol Ther 64:237–247
Greene DS, Salazar DE, Dockens RC, Kroboth P, Barbhaiya RH (1995) Coadministration of nefazodone and benzodiazepines: III. A pharmacokinetic interaction study with alprazolam. J Clin Psychopharmacol 15:399–408
Guzey C, Norstrom A, Spigset O (2002) Change from the CYP2D6 extensive metabolizer to the poor metabolizer phenotype during treatment with bupropion. Ther Drug Monit 24:436–437
Haddad PM, Anderson IM (2002) Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs 62:1649–1671
Herman BD, Fleishaker JC, Brown MT (1999) Ketoconazole inhibits the clearance of the enantiomers of the antidepressant reboxetine in humans. Clin Pharmacol Ther 66:374–379
Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr (1992) Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 52:231–238
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR (1993) Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA 269:1513–1518
Honig PK, Wortham DC, Hull R, Zamani K, Smith JE, Cantilena LR (1993) Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics. J Clin Pharmacol 33:1201–1206
http://www.legemiddelforbruk.no/English. Cited 13 August 2004)
Jalava KM, Olkkola KT, Neuvonen PJ (1996) Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone. Eur J Clin Pharmacol 51:331–334
Kennedy SH, McCann SM, Masellis M, McIntyre RS, Raskin J, McKay G, Baker GB (2002) Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry 63:181–186
Kivisto KT, Lamberg TS, Kantola T, Neuvonen PJ (1997) Plasma buspirone concentrations are greatly increased by erythromycin and itraconazole. Clin Pharmacol Ther 62:348–354
Kosoglou T, Salfi M, Lim JM, Batra VK, Cayen MN, Affrime MB (2000) Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine. Br J Clin Pharmacol 50:581–589
Kotlyar M, Brewer ER, Golding M, Carson SW (2003) Nefazodone inhibits methylprednisolone disposition and enhances its adrenal-suppressant effect. J Clin Psychopharmacol 23:652–656
LaForce CF, Szefler SJ, Miller MF, Ebling W, Brenner M (1983) Inhibition of methylprednisolone elimination in the presence of erythromycin therapy. J Allergy Clin Immunol 72:34–39
Laine K, Tybring G, Hartter S, Andersson K, Svensson JO, Widen J, Bertilsson L (2001) Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test. Clin Pharmacol Ther 70:327–335
Lam YW, Alfaro CL, Ereshefsky L, Miller M (2003) Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone. J Clin Pharmacol 43:1274–1282
Lamberg TS, Kivisto KT, Neuvonen PJ (1998) Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone. Clin Pharmacol Ther 63:640–645
Laroudie C, Salazar DE, Cosson JP, Cheuvart B, Istin B, Girault J, Ingrand I, Decourt JP (2000) Carbamazepine-nefazodone interaction in healthy subjects. J Clin Psychopharmacol 20:46–53
Macphee GJ, McInnes GT, Thompson GG, Brodie MJ (1986) Verapamil potentiates carbamazepine neurotoxicity: a clinically important inhibitory interaction. Lancet 1:700–703
Madani S, Barilla D, Cramer J, Wang Y, Paul C (2002) Effect of terbinafine on the pharmacokinetics and pharmacodynamics of desipramine in healthy volunteers identified as cytochrome P450 2D6 (CYP2D6) extensive metabolizers. J Clin Pharmacol 42:1211–1218
Miles MV, Tennison MB (1989) Erythromycin effects on multiple-dose carbamazepine kinetics. Ther Drug Monit 11:47–52
Molden E (2004) Variability in cytochrome P450-mediated metabolism of cardiovascular drugs: clinical implications and practical attempts to avoid potential problems. Heart Drug 4:55–79
Olkkola KT, Backman JT, Neuvonen PJ (1994) Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 55:481–485
Olkkola KT, Ahonen J, Neuvonen PJ (1996) The effects of the systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analg 82:511–516
Olkkola KT, Aranko K, Luurila H, Hiller A, Saarnivaara L, Himberg JJ, Neuvonen PJ (1993) A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther 53:298–305
Omar MA, Wilson JP (2002) FDA adverse event reports on statin-associated rhabdomyolysis. Ann Pharmacother 36:288–295
Osowski CL, Dix SP, Lin LS, Mullins RE, Geller RB, Wingard JR (1996) Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients. Transplantation 61:1268–1272
Ozdemir V, Naranjo CA, Herrmann N, Reed K, Sellers EM, Kalow W (1997) Paroxetine potentiates the central nervous system side effects of perphenazine: contribution of cytochrome P4502D6 inhibition in vivo. Clin Pharmacol Ther 62:334–347
Product information: Rapamune® (sirolimus) Berkshire, UK: Wyeth, September 2003
Product information: Relpax® (eletriptan) Oslo, Norway: Pfizer, December 2003
Product information: Seroquel® (quetiapine) Oslo, Norway: AstraZeneca, January 2003
Sindrup SH, Hofmann U, Asmussen J, Mikus G, Brosen K, Nielsen F, Ingwersen SH, Broen Christensen C (1996) Impact of quinidine on plasma and cerebrospinal fluid concentrations of codeine and morphine after codeine intake. Eur J Clin Pharmacol 49:503–509
Spina E, Arena D, Scordo MG, Fazio A, Pisani F, Perucca E (1997) Elevation of plasma carbamazepine concentrations by ketoconazole in patients with epilepsy. Ther Drug Monit 19:535–538
Spina E, Avenoso A, Facciola G, Scordo MG, Ancione M, Madia A (2001) Plasma concentrations of risperidone and 9-hydroxyrisperidone during combined treatment with paroxetine. Ther Drug Monit 23:223–227
Spina E, Avenoso A, Salemi M, Facciola G, Scordo MG, Ancione M, Madia A (2000) Plasma concentrations of clozapine and its major metabolites during combined treatment with paroxetine or sertraline. Pharmacopsychiatry 33:213–217
Spina E, Avenoso A, Scordo MG, Ancione M, Madia A, Gatti G, Perucca E (2002) Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. J Clin Psychopharmacol 22:419–423
Spina E, Avenoso A, Facciola G, Fabrazzo M, Monteleone P, Maj M, Perucca E, Caputi AP (1998) Effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia. Int Clin Psychopharmacol 13:141–145
van Haarst AD, van’t Klooster GA, van Gerven JM, Schoemaker RC, van Oene JC, Burggraaf J, Coene MC, Cohen AF (1998) The influence of cisapride and clarithromycin on QT intervals in healthy volunteers. Clin Pharmacol Ther 64:542–546
Varis T, Kivisto KT, Backman JT, Neuvonen PJ (1999) Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers. Pharmacol Toxicol 85:29–32
Varis T, Kivisto KT, Backman JT, Neuvonen PJ (2000) The cytochrome P450 3A4 inhibitor itraconazole markedly increases the plasma concentrations of dexamethasone and enhances its adrenal-suppressant effect. Clin Pharmacol Ther 68:487–494
Varis T, Backman JT, Kivisto KT, Neuvonen PJ (2000) Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenal-suppressant effect of oral methylprednisolone. Clin Pharmacol Ther 67:215–221
Yasui N, Tybring G, Otani K, Mihara K, Suzuki A, Svensson JO, Kaneko S (1997) Effects of thioridazine, an inhibitor of CYP2D6, on the steady-state plasma concentrations of the enantiomers of mianserin and its active metabolite, desmethylmianserin, in depressed Japanese patients. Pharmacogenetics 7:369–374
Yasui N, Otani K, Kaneko S, Ohkubo T, Osanai T, Sugawara K, Chiba K, Ishizaki T (1996) A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in alprazolam metabolism. Clin Pharmacol Ther 59:514–519
Yasui N, Kondo T, Otani K, Furukori H, Kaneko S, Ohkubo T, Nagasaki T, Sugawara K (1998) Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology (Berl) 139:269–273
Yeates RA, Laufen H, Zimmermann T (1996) Interaction between midazolam and clarithromycin: comparison with azithromycin. Int J Clin Pharmacol Ther 34:400–405
Zhang Y, Britto MR, Valderhaug KL, Wedlund PJ, Smith RA (1992) Dextromethorphan: enhancing its systemic availability by way of low-dose quinidine-mediated inhibition of cytochrome P4502D6. Clin Pharmacol Ther 51:647–655
Åsberg A, Christensen H, Hartmann A, Carlson E, Molden E, Berg KJ (1999) Pharmacokinetic interactions between microemulsion formulated cyclosporine A and diltiazem in renal transplant recipients. Eur J Clin Pharmacol 55:383–387
Acknowledgements
We are grateful to the employees at Bjørkelangen Apotek, Ullensaker Apotek and Tynset Apotek for their help and enthusiasm in the project and to Norges Apotekerforening for the financial support.
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Molden, E., Garcia, B.H., Braathen, P. et al. Co-prescription of cytochrome P450 2D6/3A4 inhibitor-substrate pairs in clinical practice. A retrospective analysis of data from Norwegian primary pharmacies. Eur J Clin Pharmacol 61, 119–125 (2005). https://doi.org/10.1007/s00228-004-0877-2
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DOI: https://doi.org/10.1007/s00228-004-0877-2