title: Age-related changes of hepatic clearances of cytochrome P450 probes, midazolam and R-/S-warfarin in combination with caffeine, omeprazole and metoprolol in cynomolgus monkeys using in vitro-in vivo correlation.
abstract: 1. Pharmacokinetics of human cytochrome P450 probes (caffeine, racemic warfarin, omeprazole, metoprolol and midazolam) were investigated after single intravenous and oral administrations at doses of 0.20 and 1.0 mg kg(-1), respectively, in combination to three young (3-year-old) and three aged (16-year-old) cynomolgus monkeys. 2. The plasma concentrations of caffeine and R-/S-warfarin decreased slowly in a monophasic manner, but those of omeprazole, metoprolol and midazolam decreased rapidly, in a similar manner to those as reported for pharmacokinetics in humans. 3. The mean maximum concentrations of R- and S-warfarin (4.6 and 3.7 µg/mL, respectively) in aged monkeys after oral administration were significantly higher than those in young monkeys (3.3 and 2.7 µg/mL). The mean clearance (CL) values of midazolam in aged monkeys (9.5 mL/min/kg) were significantly lower than those in young monkeys (13 mL/min/kg). 4. Individual intrinsic CL values for omeprazole (r = 0.29) and metoprolol (r = 0.30) of individual monkey livers were inversely correlated with their ages significantly (p < 0.05) in liver microsomes prepared from 55 cynomolgus monkeys. 5. These results suggest that cynomolgus monkeys could be a good model for humans, especially with particular characteristics in reduced CLs of some human P450 substrates by aging.
authors.affiliation: Ono Pharmaceutical Co., Ltd. , Shimamoto-cho, Mishima-gun, Osaka , Japan .
authors.forename: Takashi
authors.initials: T
authors.lastname: Koyanagi
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaura
authors.forename: Kanami
authors.initials: K
authors.lastname: Ikeda
authors.forename: Koji
authors.initials: K
authors.lastname: Yano
authors.forename: Shotaro
authors.initials: S
authors.lastname: Uehara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Utoh
authors.forename: Soonih
authors.initials: S
authors.lastname: Kim
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008252:Macaca fascicularis; D008297:Male; D008790:Metoprolol / Q000097:blood / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D023421:Models, Animal; D008954:Models, Biological; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D002110:Caffeine; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D008790:Metoprolol; D009853:Omeprazole; D008874:Midazolam
keywords: Cynomolgus monkey; hepatic clearance; in vitro–in vivo correlation; liver microsomes, P450 substrates