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Innate Immunity
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Changes of midazolam pharmacokinetics in Wistar rats treated with lipopolysaccharide: relationship between total CYP and CYP3A2

Ryuji Kato

Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan

Satoshi Yamashita

Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan

Jun Moriguchi

Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan

Machiko Nakagawa

Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan

Yuri Tsukura

Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan

Kagehiro Uchida

Biomarker Science Co., Ltd, Chuo-ku, Osaka, Japan

Fumio Amano

Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan

Yoshihiko Hirotani

Laboratory of Clinical Pharmaceutics, Faculty of Pharmacy, Osaka-Ohtani University, Tondabayashi, Japan

Yoshio Ijiri

Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan

Kazuhiko Tanaka

Laboratory of Clinical Pharmacy and Clinical Pharmacokinetics, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan, pico{at}gly.oups.ac.jp

It has been reported that infection interferes with drug metabolism, resulting in changes in pharmacokinetics. In this study, we investigated the effects of lipopolysaccharide (LPS) on hepatic total cytochrome P450 (CYP), CYP3A2, and CYP2C11 contents in a transient, LPS-induced, endotoxemia model of rats. In addition, to assess the effects on CYP3A2 activities, the pharmacokinetics of midazolam (CYP3A2 substrate) and 1-OH-midazolam (metabolite of midazolam) were investigated. Hepatic total CYP contents were significantly low until day 3 (P < 0.05) but returned to the control level on day 5. Hepatic CYP3A2 contents were significantly decreased on day 1 until day 5 (P < 0.05) but returned to the control level on day 7. Hepatic CYP2C11 contents were continuously low until day 7, and lowest on day 3. The AUC of 1-OH-midazolam was significantly decreased on day 1 after LPS administration (P < 0.01). In conclusion, LPS (5 mg/kg) challenge decreased hepatic total CYP, CYP3A2, and CYP2C11 contents and also decreased the activities of hepatic CYP3A2. It took at least 7 days for hepatic total CYP and CYP3A2 to recover to control levels, and it was suggested that the changes of hepatic total CYP contents might correlate with those of hepatic CYP3A2 contents and activities. Additionally, it is shown that their changes might reflect the recovery process from inflammation.

Key Words: Lipopolysaccharide • total CYP • CYP3A2 • CYP2C11 • liver • midazolam

Innate Immunity, Vol. 14, No. 5, 291-297 (2008)
DOI: 10.1177/1753425908095956
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