Model for the drug-drug interaction responsible for CYP3A enzyme inhibition. I: evaluation of cynomolgus monkeys as surrogates for humans

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
T KanazuM Koike

Abstract

1. Anti-human cytochrome P450 (CYP) 3A4 antiserum completely inhibited midazolam metabolism in monkey liver microsomes, suggesting that midazolam was mainly metabolized by CYP3A enzyme(s) in monkey liver microsomes. 2. Midazolam metabolism was also inhibited in vitro by typical chemical inhibitors of CYP3A, such as ketoconazole, erythromycin and diltiazem, and the apparent K(i) values for ketoconazole, erythromycin and diltiazem were 0.127, 94.2 and 29.6 microM, respectively. 3. CYP3A inhibitors increased plasma midazolam concentrations when midazolam and CYP3A inhibitors were co-administered orally. However, the pharmacokinetic parameters of midazolam were not changed by treatment with CYP3A inhibitors when midazolam was given intravenously. This suggests that CYP3A inhibitors modified the first-pass metabolism in the liver and/or intestine, but not systemic metabolism. 4. The drug-drug interaction responsible for CYP3A enzyme(s) inhibition was observed when midazolam and inhibitors were co-administrated orally. Therefore, it was concluded that monkeys given midazolam orally could be useful models for predicting drug-drug interactions in man based on CYP3A enzyme inhibition.

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Citations

Apr 30, 2010·Pharmaceutical Research·Cuyue Tang, Thomayant Prueksaritanont
Mar 19, 2009·The Journal of Pharmacology and Experimental Therapeutics·Huixia ZhangJashvant D Unadkat
May 30, 2009·The Journal of Pharmacology and Experimental Therapeutics·Huixia ZhangJashvant D Unadkat
Nov 12, 2014·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yohei Kosugi, Junzo Takahashi
Sep 27, 2007·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·S V MandlekarP H Marathe
Mar 15, 2008·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·N SekiguchiY Aso
Sep 14, 2007·Journal of Pharmaceutical Sciences·Hiroshi Komura, Masahiro Iwaki
Jan 16, 2007·Biochemical Pharmacology·Cuyue TangBrian A Carr
Jul 16, 2005·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Takushi KanazuMasahiro Koike
Aug 9, 2016·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Zuzana E HaarhoffA David Rodrigues
Oct 16, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Akihito OgasawaraKoichiro Fukuzaki
Aug 26, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Akihito OgasawaraToshiyuki Kume
Oct 17, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sean KimMichael Sinz
Jun 30, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tatsuyuki OhtsukaToshiyuki Kume
Feb 17, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Hongjian ZhangW Griffith Humphreys
Dec 5, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Akihito OgasawaraEmiko Kazama
May 2, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tomohiro NishimuraAkira Tsuji
Jun 20, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Thomayant PrueksaritanontJiunn H Lin

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