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.
Footnotes
This work was supported by the Japan Society for the Promotion of Science [Grant-in-Aid for Young Scientists (B) 22790109] and PhoenixBio, Co., Ltd.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- PK
- pharmacokinetics
- P450
- cytochrome P450
- SCID
- severe combined immunodeficiency
- h-PXB mice
- human chimeric mice
- UGT
- UDP-glucuronosyltransferase
- SULT
- sulfotransferase
- r-PXB mice
- rat chimeric mice
- RI
- replacement index
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry.
- Received June 27, 2012.
- Accepted August 30, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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