1. In vivo evaluation of intestinal human CYP3A inhibition by macrolide antibiotics in CYP3A-humanised mice.
- Author
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Minegishi, Genki, Kazuki, Yasuhiro, Nitta, Shin-Ichiro, Miyajima, Atsushi, Akita, Hidetaka, and Kobayashi, Kaoru
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MACROLIDE antibiotics , *CLARITHROMYCIN , *INTESTINES , *DRUG interactions , *ARTIFICIAL chromosomes , *ERYTHROMYCIN , *CYTOCHROME P-450 CYP3A - Abstract
It is important to predict drug-drug interactions via inhibition of intestinal cytochrome P450 3A (CYP3A) which is a determinant of bioavailability of orally administered CYP3A substrates. However, inhibitory effects of macrolide antibiotics on CYP3A-mediated metabolism are not entirely identical between humans and rodents. We investigated the effects of macrolide antibiotics, clarithromycin and erythromycin, on in vitro and in vivo metabolism of triazolam, a CYP3A substrate, in CYP3A-humanised mice generated by using a mouse artificial chromosome vector carrying a human CYP3A gene. Metabolic activities of triazolam were inhibited by macrolide antibiotics in liver and intestine microsomes of CYP3A-humanised mice. The area under the plasma concentration-time curve ratios of 4-hydroxytriazolam to triazolam after oral dosing of triazolam were significantly decreased by multiple administration of macrolide antibiotics. The plasma concentrations ratios of α-hydroxytriazolam and 4-hydroxytriazolam to triazolam in portal blood were significantly decreased by multiple administration of clarithromycin in CYP3A-humanised mice. These results suggest that intestinal CYP3A activity was inhibited by macrolide antibiotics in CYP3A-humanised mice in vitro and in vivo. The plasma concentrations of triazolam and its metabolites in the portal blood of CYP3A-humanised mice would be useful for direct evaluation of intestinal CYP3A-mediated drug-drug interactions. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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