title: Simultaneous pharmacokinetics evaluation of human cytochrome P450 probes, caffeine, warfarin, omeprazole, metoprolol and midazolam, in common marmosets (Callithrix jacchus).
abstract: 1. Pharmacokinetics of human cytochrome P450 probes (caffeine, racemic warfarin, omeprazole, metoprolol and midazolam) composite, after single intravenous and oral administrations at doses of 0.20 and 1.0 mg kg(-1), respectively, to four male common marmosets were investigated. 2. The plasma concentrations of caffeine and warfarin decreased slowly in a monophasic manner but those of omeprazole, metoprolol and midazolam decreased extensively after intravenous and oral administrations, in a manner that approximated those as reported for pharmacokinetics in humans. 3. Bioavailabilities were ∼100% for caffeine and warfarin, but <25% for omeprazole and metoprolol. Bioavailability of midazolam was 4% in marmosets, presumably because of contribution of marmoset P450 3A4 expressed in small intestine and liver, with a high catalytic efficiency for midazolam 1'-hydroxylation as evident in the recombinant system. 4. These results suggest that common marmosets, despite their rapid clearance of some human P450 probe substrates, could be an experimental model for humans and that marmoset P450s have functional characteristics that differ from those of human and/or cynomolgus monkey P450s in some aspects, indicating their importance in modeling in P450-dependent drug metabolism studies in marmosets and of further studies.
authors.affiliation: a Showa Pharmaceutical University , Machida, Tokyo , Japan .
authors.forename: Shotaro
authors.initials: S
authors.lastname: Uehara
authors.affiliation: b Marmoset Research Department, Central Institute for Experimental Animals , Kawasaki , Japan .
authors.forename: Takashi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: a Showa Pharmaceutical University , Machida, Tokyo , Japan .|c Shin Nippon Biomedical Laboratories, Ltd. , Kainan, Wakayama , Japan .
authors.forename: Masahiro
authors.initials: M
authors.lastname: Utoh
authors.affiliation: c Shin Nippon Biomedical Laboratories, Ltd. , Kainan, Wakayama , Japan .
authors.forename: Akiko
authors.initials: A
authors.lastname: Toda
authors.affiliation: a Showa Pharmaceutical University , Machida, Tokyo , Japan .
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: c Shin Nippon Biomedical Laboratories, Ltd. , Kainan, Wakayama , Japan .
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uno
authors.affiliation: d Center of Applied Developmental Biology, Central Institute for Experimental Animals , Kawasaki , Japan , and.|e Keio Advanced Research Center, Keio University , Minato-Ku, Tokyo , Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Sasaki
authors.affiliation: a Showa Pharmaceutical University , Machida, Tokyo , Japan .
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics*; D002144:Callithrix / Q000378:metabolism; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008790:Metoprolol / Q000097:blood / Q000493:pharmacokinetics*; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D023421:Models, Animal; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D002110:Caffeine; D014859:Warfarin; D051544:Cytochrome P-450 CYP3A; D008790:Metoprolol; D009853:Omeprazole; D008874:Midazolam
keywords: CYP3A4; P450 substrates; hepatic clearance; human; marmoset