RT Journal Article
SR Electronic
T1 Predictability of Metabolism of Ibuprofen and Naproxen Using Chimeric Mice with Human Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2267
OP 2272
DO 10.1124/dmd.112.047555
VO 40
IS 12
A1 Seigo Sanoh
A1 Aya Horiguchi
A1 Kazumi Sugihara
A1 Yaichiro Kotake
A1 Yoshitaka Tayama
A1 Naoto Uramaru
A1 Hiroki Ohshita
A1 Chise Tateno
A1 Toru Horie
A1 Shigeyuki Kitamura
A1 Shigeru Ohta
YR 2012
UL http://dmd.aspetjournals.org/content/40/12/2267.abstract
AB 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.