Model for the drug-drug interaction responsible for CYP3A enzyme inhibition. II: establishment and evaluation of dexamethasone-pretreated female rats

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Takushi KanazuMasahiro Koike

Abstract

1. Cytochrome P450 (CYP) 3A catalysis of testosterone 6beta-hydroxylation in female rat liver microsomes was significantly induced, then reached a plateau level after pretreatment with 80 mg kg(-1) day(-1) dexamethasone (DEX) for 3 days. 2. Midazolam was mainly metabolized by CYP3A in DEX-treated female rat liver microsomes from an immuno-inhibition study, and the apparent K(m) was 1.8 microM, similar to that in human microsomes. 3. Ketoconazole and erythromycin, typical CYP3A inhibitors, demonstrated extensive inhibition of midazolam metabolism in DEX-treated female rat liver microsomes, and the apparent K(i) values were 0.088 and 91.2 microM, respectively. The values were similar to those in humans, suggesting that DEX-treated female rat liver microsomes have properties similar to those of humans. 4. After oral administration of midazolam, the plasma midazolam concentration in DEX-treated female rats significantly decreased compared with control female rats. The area under the plasma concentration curve (AUC) and elimination half-life were one-11th and one-20th of those of control female rats, respectively. 5. Using DEX-treated female rats, the effect of CYP3A inhibitors on midazolam pharmacokinetics was evaluated. The AUC an...Continue Reading

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Citations

Mar 15, 2008·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·N SekiguchiY Aso
Feb 7, 2012·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·John H K Yeung, Penelope M Y Or
Jul 20, 2010·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Xin WangJohn H K Yeung
Mar 23, 2011·Phytotherapy Research : PTR·Xin Wang, John H K Yeung
May 12, 2012·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Ragini VuppugallaPunit H Marathe
Jul 16, 2005·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Takushi KanazuMasahiro Koike
Nov 12, 2014·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yohei Kosugi, Junzo Takahashi
May 9, 2015·Journal of Pharmacological Sciences·Shan XiongZhenqing Zhang
Nov 8, 2011·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Xin Wang, John Hok-Keung Yeung
Aug 2, 2017·Asian Pacific Journal of Tropical Medicine·Sunday O NdukaChinwe V Ukwe

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