title: Human plasma concentrations of cytochrome P450 probe cocktails extrapolated from pharmacokinetics in mice transplanted with human hepatocytes and from pharmacokinetics in common marmosets using physiologically based pharmacokinetic modeling.
abstract: 1. The pharmacokinetic data of cytochrome P450 probes in humans can be extrapolated from corresponding data in cynomolgus monkeys, dogs and minipigs using simplified physiologically based pharmacokinetic (PBPK) modeling. In this study, the modeling methodology was further adapted to estimate human plasma concentrations of P450 probes based on data from mice transplanted with human hepatocytes or based on data from marmosets. 2. Using known species allometric scaling factors, the observed plasma concentrations of caffeine, warfarin, omeprazole, metoprolol, and midazolam in chimeric TK-NOG mice with humanized liver were scaled to human oral monitoring equivalents. Using the same approach, the previously reported pharmacokinetics of the five P450 probes in marmosets were also scaled to reported equivalents in humans using in vitro metabolic clearance data. 3. Human plasma concentration profiles of the five P450 probes estimated by simplified human PBPK models based on the observed pharmacokinetics in mice with humanized liver and on the reported pharmacokinetics in marmosets were consistent with previously published pharmacokinetic data in Caucasians. 4. These results suggest that mice with humanized liver and/or marmosets could be suitable pharmacokinetic models for humans during research into new drugs, especially when used in combination with simple PBPK models.
authors.affiliation: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Japan.|b Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd , Kainan , Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Utoh
authors.affiliation: c Laboratory of Animal Research Department , and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.affiliation: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Japan.
authors.forename: Marina
authors.initials: M
authors.lastname: Mitsui
authors.affiliation: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Japan.
authors.forename: Mirai
authors.initials: M
authors.lastname: Kawano
authors.affiliation: b Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd , Kainan , Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Toda
authors.affiliation: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Uehara
authors.affiliation: b Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd , Kainan , Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uno
authors.affiliation: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: d Marmoset Research Department, Central Institute for Experimental Animals , Kawasaki , Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Sasaki
authors.affiliation: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D000818:Animals; D002110:Caffeine / Q000493:pharmacokinetics; D002678:Chimera; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008874:Midazolam / Q000493:pharmacokinetics; D008954:Models, Biological; D009853:Omeprazole / Q000493:pharmacokinetics; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D013552:Swine; D013556:Swine, Miniature; D014859:Warfarin / Q000493:pharmacokinetics
chemical_list: D004364:Pharmaceutical Preparations; D002110:Caffeine; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D009853:Omeprazole; D008874:Midazolam
keywords: Hepatic clearance; P450 substrates; PBPK modeling