Impact of nonlinear midazolam pharmacokinetics on the magnitude of the midazolam-ketoconazole interaction in rats

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Ragini VuppugallaPunit H Marathe

Abstract

Numerous groups have described the rat as an in vivo model for the assessment and prediction of drug-drug interactions (DDIs) in humans involving the inhibition of cytochrome P450 3A forms. Even for a well-established substrate-inhibitor pair like midazolam-ketoconazole, however, the magnitude of the DDI in rats (e.g. 1.5- to 5-fold) does not relate to what is observed clinically (e.g. 5- to 16-fold). Because nonlinear substrate pharmacokinetics (PK) may result in a weaker interaction, it was hypothesized that the lower magnitude of interaction observed in rats was due to the saturation of metabolic pathway(s) of midazolam at the doses used (10-20 mg/kg). Therefore, the inhibitory effects of ketoconazole were reevaluated at lower oral (1 and 5 mg/kg) and intravenous (IV) (1 mg/kg) doses of midazolam. In support of the hypothesis, oral exposure at 5 mg/kg dose of midazolam was 18-fold higher compared to that at 1 mg/kg. Furthermore, when the interaction was investigated at the lower midazolam dose (1 mg/kg), ketoconazole increased the IV and oral exposure of midazolam by 7-fold and 11-fold, respectively. A weaker DDI (1.5- to 1.8-fold) was observed at the higher oral midazolam dose. Collectively, these results suggest that the l...Continue Reading

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Citations

May 28, 2013·Evidence-based Complementary and Alternative Medicine : ECAM·Xin TianHai-Ling Qiao
Jul 23, 2013·Biopharmaceutics & Drug Disposition·Nathalie RiouxJianmin Duan
Jan 8, 2014·Biopharmaceutics & Drug Disposition·Shinya UchidaNoriyuki Namiki
Apr 15, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Rowan A StringerBindi Sohal
Jan 19, 2021·Biomedical Chromatography : BMC·Sara Batista do NascimentoWhocely Victor de Castro

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