alexa Effect of ursodeoxycholic acid on the pharmacokinetics of midazolam and CYP3A in the liver and intestine of rats.
Pharmaceutical Sciences

Pharmaceutical Sciences

Pharmaceutica Analytica Acta

Author(s): Kurosawa S, Uchida S, Ito Y, Yamada S

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Abstract 1. The elimination half-life of midazolam administered intravenously (5 mg kg(-1)) or orally (15 mg kg(-1)) was significantly decreased by 70\% and 73\%, respectively, 24 h after a single oral administration of ursodeoxycholic acid (UDCA, 300 mg kg(-1)) in rats. In the liver there was a significant enhancement of the hydroxylation of midazolam in the microsomes and expression of cytochrome P450 (CYP) 3A1 messenger RNA (mRNA) and CYP3A2 mRNA. 2. The C(max) and area under the curve (AUC)(0-infinity) of midazolam were significantly (1.8-2.3 fold) increased by the single oral treatment with UDCA (100 and 300 mg kg(-1)). Thus, the oral bioavailability, estimated from the AUC(0-infinity), of midazolam administered intravenously and orally was significantly (1.8- and 2.3-fold, respectively) increased by the treatment with UDCA. 3. Repeated administration of UDCA (300 mg kg(-1) day(-1)) for 7 days did not alter the pharmacokinetics of midazolam administered intravenously or orally, and the expression of mRNA for CYP3As in the rat liver. 4. The study has shown that a single administration of UDCA in rats induces significant hepatic CYP3A activity and increases significantly the oral bioavailability of midazolam. Such effects on the pharmacokinetics of midazolam were little observed on the repeated administration of UDCA. This article was published in Xenobiotica and referenced in Pharmaceutica Analytica Acta

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