title: Predictability of metabolism of ibuprofen and naproxen using chimeric mice with human hepatocytes.
abstract: Prediction of human drug metabolism is important for drug development. Recently, the number of new drug candidates metabolized by not only cytochrome P450 (P450) but also non-P450 has been increasing. It is necessary to consider species differences in drug metabolism between humans and experimental animals. We examined species differences of drug metabolism, especially between humans and rats, for ibuprofen and (S)-naproxen as nonsteroidal anti-inflammatory drugs, which are metabolized by P450 and UDP-glucuronosyltransferase, sulfotransferase, and amino acid N-acyltransferase for taurine conjugation in liver, using human chimeric mice (h-PXB mice) repopulated with human hepatocytes and rat chimeric mice (r-PXB mice) transplanted with rat hepatocytes. We performed the direct comparison of excretory metabolites in urine between h-PXB mice and reported data for humans as well as between r-PXB mice and rats after administration of ibuprofen and (S)-naproxen. Good agreement for urinary metabolites (percentage of dose) was observed not only between humans and h-PXB mice but also between rats and r-PXB mice. Therefore, the metabolic profiles in humans and rats reflected those in h-PXB mice and r-PXB mice. Our results indicated that h-PXB mice should be helpful for predicting the quantitative metabolic profiles of drugs mediated by P450 and non-P450 in liver, and r-PXB mice should be helpful for evaluation of species differences in these metabolic enzymes.
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan. sanoh@hiroshima-u.ac.jp
authors.forename: Seigo
authors.initials: S
authors.lastname: Sanoh
authors.forename: Aya
authors.initials: A
authors.lastname: Horiguchi
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sugihara
authors.forename: Yaichiro
authors.initials: Y
authors.lastname: Kotake
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tayama
authors.forename: Naoto
authors.initials: N
authors.lastname: Uramaru
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohshita
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.forename: Toru
authors.initials: T
authors.lastname: Horie
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kitamura
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D002678:Chimera / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007052:Ibuprofen / Q000378:metabolism*; D008658:Inactivation, Metabolic / Q000502:physiology*; D008297:Male; D055442:Metabolome; D051379:Mice; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009288:Naproxen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D009288:Naproxen; D003577:Cytochrome P-450 Enzyme System; D007052:Ibuprofen