Are Circulating Metabolites Important in Drug–Drug Interactions?: Quantitative Analysis of Risk Prediction and Inhibitory Potency

The potential of metabolites to contribute to drug–drug interactions (DDIs) is not well defined. The aim of this study was to determine the quantitative role of circulating metabolites in inhibitory DDIs in vivo. The area under the plasma concentration–time curve (AUC) data related to at least one circulating metabolite was available for 71% of the 102 inhibitor drugs identified. Of the 80 metabolites characterized at steady state, 78% had AUCs >10% of that of the parent drug. A comparison of the inhibitor concentration/inhibition constant ([I]/Ki) ratios of metabolites and the respective parent drugs showed that 17 of the 21 (80%) reversible inhibitors studied had metabolites that were likely to contribute to in vivo DDIs, with some metabolites predicted to have inhibitory effects greater than those of the parent drug. The in vivo drug interaction risks associated with amiodarone, bupropion, and sertraline could be identified from in vitro data only, when data pertaining to metabolites were included in the predictions. In conclusion, cytochrome P450 (CYP) inhibitors often have circulating metabolites that contribute to clinically observed CYP inhibition.

[1]  G. Tucker,et al.  Potent inhibition of yeast-expressed CYP2D6 by dihydroquinidine, quinidine, and its metabolites. , 1995, Biochemical pharmacology.

[2]  C. Yeung,et al.  Qualitative Analysis of the Role of Metabolites in Inhibitory Drug‐Drug Interactions: literature evaluation based on the Metabolism and Transport Drug Interaction Database , 2009, Chemical research in toxicology.

[3]  Julia Qiu,et al.  Interactions of Human P-glycoprotein with Simvastatin, Simvastatin Acid, and Atorvastatin , 2004, Pharmaceutical Research.

[4]  Grant T Generaux,et al.  An in Vitro Mechanistic Study to Elucidate the Desipramine/Bupropion Clinical Drug-Drug Interaction , 2008, Drug Metabolism and Disposition.

[5]  Kiyomi Ito,et al.  IMPACT OF PARALLEL PATHWAYS OF DRUG ELIMINATION AND MULTIPLE CYTOCHROME P450 INVOLVEMENT ON DRUG-DRUG INTERACTIONS: CYP2D6 PARADIGM , 2005, Drug Metabolism and Disposition.

[6]  D. Greenblatt,et al.  Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. , 1997, Journal of clinical psychopharmacology.

[7]  C. Masimirembwa,et al.  Inhibitory effects of antiparasitic drugs on cytochrome P450 2D6 , 2004, European Journal of Clinical Pharmacology.

[8]  Sara K Quinney,et al.  Semiphysiologically Based Pharmacokinetic Models for the Inhibition of Midazolam Clearance by Diltiazem and Its Major Metabolite , 2009, Drug Metabolism and Disposition.

[9]  S. Shoaf,et al.  Tolvaptan Administration Does Not Affect Steady State Amiodarone Concentrations in Patients With Cardiac Arrhythmias , 2005, Journal of cardiovascular pharmacology and therapeutics.

[10]  R. Bergstrom,et al.  Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction , 1992, Clinical pharmacology and therapeutics.

[11]  E. Skjelbo,et al.  Inhibitors of imipramine metabolism by human liver microsomes. , 1992, British journal of clinical pharmacology.

[12]  Kaoru Kobayashi,et al.  The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes. , 1995, British journal of clinical pharmacology.

[13]  E. Sellers,et al.  Inhibition by fluoxetine of cytochrome P450 2D6 activity , 1993, Clinical pharmacology and therapeutics.

[14]  T. Kamataki,et al.  Oxidative metabolism of omeprazole in human liver microsomes: cosegregation with S-mephenytoin 4'-hydroxylation. , 1993, The Journal of pharmacology and experimental therapeutics.

[15]  E. Sellers,et al.  Venlafaxine oxidation in vitro is catalysed by CYP2D6. , 1996, British journal of clinical pharmacology.

[16]  J S Harmatz,et al.  Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. , 1994, The Journal of pharmacology and experimental therapeutics.

[17]  R. Bergstrom,et al.  The effect of sertraline on the pharmacokinetics of desipramine and imipramine , 1997, Clinical pharmacology and therapeutics.

[18]  J. Alderman.  Coadministration of sertraline with cisapride or pimozide: an open-label, nonrandomized examination of pharmacokinetics and corrected QT intervals in healthy adult volunteers. , 2005, Clinical therapeutics.

[19]  R. O'Reilly.  Stereoselective Interaction of Sulfinpyrazone with Racemic Warfarin and Its Separated Enantiomorphs in Man , 1982, Circulation.

[20]  B. W. Penman,et al.  Use of cDNA-expressed human cytochrome P450 enzymes to study potential drug-drug interactions. , 1997, Advances in pharmacology.

[21]  Zhi-xiang Shen,et al.  Effects of imatinib (Glivec) on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in Chinese patients with chronic myelogenous leukaemia. , 2008, British journal of clinical pharmacology.

[22]  J. Frölich,et al.  Plasma levels of sulfinpyrazone and of two of its metabolites after a single dose and during the steady state , 2004, European Journal of Clinical Pharmacology.

[23]  L. Meurling,et al.  Effect of ketoconazole on venlafaxine plasma concentrations in extensive and poor metabolisers of debrisoquine , 2003, European Journal of Clinical Pharmacology.

[24]  H. Yamazaki,et al.  Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: prediction of in vivo drug interactions. , 2000, British journal of clinical pharmacology.

[25]  C. Masimirembwa,et al.  Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[26]  J. Houston,et al.  In vitro cytochrome P450 inhibition data and the prediction of drug‐drug interactions: Qualitative relationships, quantitative predictions, and the rank‐order approach , 2005, Clinical pharmacology and therapeutics.

[27]  W. L. Nelson,et al.  ROLE OF ITRACONAZOLE METABOLITES IN CYP3A4 INHIBITION , 2004, Drug Metabolism and Disposition.

[28]  S. Wrighton,et al.  Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. , 1993, The Journal of pharmacology and experimental therapeutics.

[29]  P. Kollman,et al.  Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[30]  P. Neuvonen,et al.  Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid , 1996, Clinical pharmacology and therapeutics.

[31]  D. Holt,et al.  The digoxin-amiodarone interaction , 1989, Cardiovascular Drugs and Therapy.

[32]  J S Harmatz,et al.  Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. , 1996, The Journal of pharmacology and experimental therapeutics.

[33]  T. Schaberg,et al.  Interaction study of lomefloxacin and ciprofloxacin with omeprazole and comparative pharmacokinetics , 1995, Antimicrobial agents and chemotherapy.

[34]  D. Flockhart,et al.  Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol. , 2001, British journal of clinical pharmacology.

[35]  D. Tweedie,et al.  Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions. , 2000, British journal of clinical pharmacology.

[36]  R. Poland,et al.  Effect of venlafaxine on imipramine metabolism , 2000, Psychiatry Research.

[37]  W. Trager,et al.  Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans , 1987, Clinical pharmacology and therapeutics.

[38]  F. Lakehal,et al.  Carbamazepine and oxcarbazepine decrease phenytoin metabolism through inhibition of CYP2C19 , 2002, Epilepsy Research.

[39]  K. Brøsen,et al.  Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine. , 1999, British journal of clinical pharmacology.

[40]  G. Tucker,et al.  Inhibition of CYP2D6 activity by treatment with propranolol and the role of 4-hydroxy propranolol. , 1994, British journal of clinical pharmacology.

[41]  A. Somogyi,et al.  The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans , 1996, Clinical pharmacology and therapeutics.

[42]  J. Houston,et al.  Diazepam-omeprazole inhibition interaction: an in vitro investigation using human liver microsomes. , 1996, British journal of clinical pharmacology.

[43]  C. Funck-Brentano,et al.  Inhibition by omeprazole of proguanil metabolism: mechanism of the interaction in vitro and prediction of in vivo results from the in vitro experiments. , 1997, The Journal of pharmacology and experimental therapeutics.

[44]  E. Burton,et al.  Prediction of in vivo drug interactions with eplerenone in man from in vitro metabolic inhibition data , 2004, Xenobiotica; the fate of foreign compounds in biological systems.

[45]  J. Alderman.  Coadministration of scrtraline with cisapride or pimozide: an open-label, nonrandomized examination of pharmacokinetics and corrected qt intervals in healthy adult volunteers , 2005 .

[46]  S. Hall,et al.  Prediction of the Effect of Erythromycin, Diltiazem, and Their Metabolites, Alone and in Combination, on CYP3A4 Inhibition , 2009, Drug Metabolism and Disposition.

[47]  Hayley S. Brown,et al.  Prediction of in vivo drug-drug interactions from in vitro data: impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant. , 2005, British journal of clinical pharmacology.

[48]  M. Danhof,et al.  Influence of single- and multiple-dose omeprazole treatment on nifedipine pharmacokinetics and effects in healthy subjects , 2004, European Journal of Clinical Pharmacology.

[49]  J. Gillespie,et al.  Atomoxetine Hydrochloride: Clinical Drug-Drug Interaction Prediction and Outcome , 2004, Journal of Pharmacology and Experimental Therapeutics.

[50]  S. Preskorn,et al.  Fluoxetine Pharmacokinetics and Effect on CYP2C19 in Young and Elderly Volunteers , 2001, Journal of clinical psychopharmacology.

[51]  P. Neuvonen,et al.  ABCB1 Haplotypes Differentially Affect the Pharmacokinetics of the Acid and Lactone Forms of Simvastatin and Atorvastatin , 2008, Clinical pharmacology and therapeutics.