Quantitative Prediction of Macrolide Drug-drug Interaction Potential from in Vitro Studies Using Testosterone As the Human Cytochrome P4503A Substrate

Overview

Journal Eur J Clin Pharmacol

Specialty Pharmacology

Date 2006 Jan 18

PMID 16416302

Citations 27

Authors

Thomas M Polasek

John O Miners

Affiliations

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Abstract

Objective: Macrolide antibiotics are mechanism-based inactivators of CYP3A enzymes that exhibit varying degrees of inhibitory potency. Our aim was to predict quantitatively the drug-drug interaction (DDI) potential of five macrolides from in vitro studies using testosterone as the CYP3A substrate, and to compare the predictions generated from human liver microsomal and recombinant CYP3A4 data.

Methods: The in vitro kinetic constants of CYP3A inactivation (K (I) and k (inact)) were estimated by varying the time of pre-incubation and the concentration of troleandomycin, erythromycin, clarithromycin, roxithromycin or azithromycin. CYP3A activity was determined from the measurement of testosterone 6beta-hydroxylation with human liver microsomes (HLM) and recombinant CYP3A4 as the enzyme sources. The mechanism-based pharmacokinetic model was fitted with inactivation data to predict the increase in oral area under the plasma concentration-time curve (AUC) for midazolam.

Results: All five macrolides inactivated testosterone 6beta-hydroxylation by HLM and recombinant CYP3A4 with k (inact) values in the range of 0.023 to 0.058 min(-1). The potency of inactivation (K (I)) was higher using recombinant CYP3A4 as the enzyme source. The oral AUCs for midazolam were predicted from HLM data to increase 16.6, 5.3, 4.6, 1.6 and 1.2-fold due to the inhibition of metabolic clearance by troleandomycin, erythromycin, clarithromycin, roxithromycin and azithromycin, respectively. These results are within the range of the AUC ratios reported for clinical DDI studies. The predicted AUC increases generated using recombinant CYP3A4 overestimated the magnitude of the DDIs.

Conclusions: The DDI potential of five macrolide antibiotics was quantitatively predicted from in vitro studies using testosterone as the CYP3A substrate with HLM as the enzyme source.

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References

PERITI P, Mazzei T, Mini E, Novelli A . Pharmacokinetic drug interactions of macrolides. Clin Pharmacokinet. 1992; 23(2):106-31. DOI: 10.2165/00003088-199223020-00004. View

Kenworthy K, Clarke S, Andrews J, Houston J . Multisite kinetic models for CYP3A4: simultaneous activation and inhibition of diazepam and testosterone metabolism. Drug Metab Dispos. 2001; 29(12):1644-51. View

Olkkola K, Aranko K, Luurila H, Hiller A, Saarnivaara L, Himberg J . A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther. 1993; 53(3):298-305. DOI: 10.1038/clpt.1993.25. View

Pessayre D, Larrey D, Vitaux J, Breil P, Belghiti J, Benhamou J . Formation of an inactive cytochrome P-450 Fe(II)-metabolite complex after administration of troleandomycin in humans. Biochem Pharmacol. 1982; 31(9):1699-704. DOI: 10.1016/0006-2952(82)90671-2. View

Westlind-Johnsson A, Malmebo S, Johansson A, Otter C, Andersson T, Johansson I . Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos. 2003; 31(6):755-61. DOI: 10.1124/dmd.31.6.755. View

Zimmermann T, Yeates R, Laufen H, Scharpf F, Leitold M, Wildfeuer A . Influence of the antibiotics erythromycin and azithromycin on the pharmacokinetics and pharmacodynamics of midazolam. Arzneimittelforschung. 1996; 46(2):213-7. View

Franklin M . Cytochrome P450 metabolic intermediate complexes from macrolide antibiotics and related compounds. Methods Enzymol. 1991; 206:559-73. DOI: 10.1016/0076-6879(91)06126-n. View

Patki K, von Moltke L, Greenblatt D . In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5. Drug Metab Dispos. 2003; 31(7):938-44. DOI: 10.1124/dmd.31.7.938. View

Wang R, Newton D, Liu N, Atkins W, Lu A . Human cytochrome P-450 3A4: in vitro drug-drug interaction patterns are substrate-dependent. Drug Metab Dispos. 2000; 28(3):360-6. View

10.

Polasek T, Elliot D, Lewis B, Miners J . Mechanism-based inactivation of human cytochrome P4502C8 by drugs in vitro. J Pharmacol Exp Ther. 2004; 311(3):996-1007. DOI: 10.1124/jpet.104.071803. View

11.

Yeates R, Laufen H, Zimmermann T . Interaction between midazolam and clarithromycin: comparison with azithromycin. Int J Clin Pharmacol Ther. 1996; 34(9):400-5. View

12.

Schuetz E, Yasuda K, Arimori K, Schuetz J . Human MDR1 and mouse mdr1a P-glycoprotein alter the cellular retention and disposition of erythromycin, but not of retinoic acid or benzo(a)pyrene. Arch Biochem Biophys. 1998; 350(2):340-7. DOI: 10.1006/abbi.1997.0537. View

13.

Silverman R . Mechanism-based enzyme inactivators. Methods Enzymol. 1995; 249:240-83. DOI: 10.1016/0076-6879(95)49038-8. View

14.

Zhou S, Chan E, Lim L, Boelsterli U, Li S, Wang J . Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4. Curr Drug Metab. 2004; 5(5):415-42. DOI: 10.2174/1389200043335450. View

15.

Pauli-Magnus C, von Richter O, Burk O, Ziegler A, Mettang T, Eichelbaum M . Characterization of the major metabolites of verapamil as substrates and inhibitors of P-glycoprotein. J Pharmacol Exp Ther. 2000; 293(2):376-82. View

16.

Backman J, Aranko K, Himberg J, Olkkola K . A pharmacokinetic interaction between roxithromycin and midazolam. Eur J Clin Pharmacol. 1994; 46(6):551-5. DOI: 10.1007/BF00196114. View

17.

Galetin A, Clarke S, Houston J . Multisite kinetic analysis of interactions between prototypical CYP3A4 subgroup substrates: midazolam, testosterone, and nifedipine. Drug Metab Dispos. 2003; 31(9):1108-16. DOI: 10.1124/dmd.31.9.1108. View

18.

Yamano K, Yamamoto K, Katashima M, Kotaki H, Takedomi S, Matsuo H . Prediction of midazolam-CYP3A inhibitors interaction in the human liver from in vivo/in vitro absorption, distribution, and metabolism data. Drug Metab Dispos. 2001; 29(4 Pt 1):443-52. View

19.

Venkatakrishnan K, Obach R . In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude. Drug Metab Dispos. 2005; 33(6):845-52. DOI: 10.1124/dmd.105.004077. View

20.

Kanamitsu S, Ito K, Green C, Tyson C, Shimada N, Sugiyama Y . Prediction of in vivo interaction between triazolam and erythromycin based on in vitro studies using human liver microsomes and recombinant human CYP3A4. Pharm Res. 2000; 17(4):419-26. DOI: 10.1023/a:1007572803027. View