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Drug Metabolism and Disposition Fast Forward
First published on August 8, 2006; DOI: 10.1124/dmd.106.011627

0090-9556/06/3411-1803-1805$20.00
DMD 34:1803-1805, 2006

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SHORT COMMUNICATION

Rat Cytochrome P450 2C11 in Liver Microsomes Involved in Oxidation of Anesthetic Agent Propofol and Deactivated by Prior Treatment with Propofol

Hiroshi Yamazaki, Makiko Shimizu, Takashi Nagashima, Masaki Minoshima, and Norie Murayama

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan

Propofol (2,6-diisopropylphenol) is a widely-used anesthetic agent attributable to its rapid biotransformation. Liver microsomal cytochrome P450 (P450) isoforms involved in the biotransformation of propofol in rats and the effects of propofol in vivo on P450 levels in rats were investigated. Of six cDNA-expressed rat P450 isoforms tested, CYP2B1 and CYP2C11 had high catalytic activities from 5 µM and 20 µM propofol concentrations, respectively. Rates of propofol metabolism, at a substrate concentration of 20 µM based on the reported human blood concentration, were decreased by intraperitoneal treatment of propofol with male rats, in contrast to a strong induction by phenobarbital. Single intravenously administered propofol (10 mg/kg) caused the decrease of total P450 and CYP2C contents and activities of testosterone 16{alpha}-hydroxylation and propofol metabolism in liver microsomes from male rats. The suppressive effects were caused by administered propofol (10 mg/kg) twice every 4 h on CYP2B activities such as testosterone 16ß-hydroxylation or pentoxyresorufin O-depentylation, in addition to the strong suppression of CYP2C function by the single propofol treatment. These results suggest that CYP2C11, presumably deactivated by propofol, has an important role in propofol metabolism in rat liver microsomes. Repeated administration of propofol could markedly decrease the biotransformation of propofol via P450 deactivation.

Address correspondence to:Prof. Dr. Hiroshi Yamazaki, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan. E-mail: hyamazak{at}ac.shoyaku.ac.jp






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