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Survey of Drug Oxidation Activities in Hepatic and Intestinal Microsomes of Individual Common Marmosets, a New Nonhuman Primate Animal Model

[ Vol. 20 , Issue. 2 ]

Author(s):

Shotaro Uehara, Toru Oshio, Kazuyuki Nakanishi, Etsuko Tomioka, Miyu Suzuki, Takashi Inoue, Yasuhiro Uno, Erika Sasaki and Hiroshi Yamazaki*   Pages 103 - 113 ( 11 )

Abstract:


Background: Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. Information for major drug-metabolizing cytochrome P450 (P450) enzymes is now available that supports the use of this primate species as an animal model for drug development. Here, we collect and provide an overview of information on the activities of common marmoset hepatic and intestinal microsomes with respect to 28 typical human P450 probe oxidations.

Results: Marmoset P450 2D6/8-dependent R-metoprolol O-demethylation activities in hepatic microsomes were significantly correlated with those of midazolam 1′- and 4-hydroxylations, testosterone 6β-hydroxylation, and progesterone 6β-hydroxylation, which are probe reactions for marmoset P450 3A4/5/90. In marmosets, the oxidation activities of hepatic microsomes and intestinal microsomes were roughly comparable for midazolam and terfenadine. Overall, multiple forms of marmoset P450 enzymes in livers and intestines had generally similar substrate recognition functionalities to those of human and/or cynomolgus monkey P450 enzymes.

Conclusion: The marmoset could be a model animal for humans with respect to the first-pass extraction of terfenadine and related substrates. These findings provide a foundation for understanding individual pharmacokinetic and toxicological results in nonhuman primates as preclinical models and will help to further support understanding of the molecular mechanisms of human P450 function.

Keywords:

Marmoset, CYP3A4, CYP2D6, CYP2C19, Polymorphism, PBPK.

Affiliation:

Showa Pharmaceutical University, Machida, Tokyo 194-8543, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Department of Marmoset Research, Central Institute for Experimental Animals, Kawasaki, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan, and 4 Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Department of Marmoset Research, Central Institute for Experimental Animals, Kawasaki, Showa Pharmaceutical University, Machida, Tokyo 194-8543



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