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In silico and in vitro pharmacogenetic analysis in mice PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Guo, Y., Lu, P., Farrell, E., Zhang, X., Weller, P., Monshouwer, M., Wang, J., Liao, G., Zhang, Z., Hu, S., Allard, J., Shafer, S., Usuka, J., Peltz, G. 2007; 104 (45): 17735-17740

Abstract

Combining the experimental efficiency of a murine hepatic in vitro drug biotransformation system with in silico genetic analysis produces a model system that can rapidly analyze interindividual differences in drug metabolism. This model system was tested by using two clinically important drugs, testosterone and irinotecan, whose metabolism was previously well characterized. The metabolites produced after these drugs were incubated with hepatic in vitro biotransformation systems prepared from the 15 inbred mouse strains were measured. Strain-specific differences in the rate of 16 alpha-hydroxytestosterone generation and irinotecan glucuronidation correlated with the pattern of genetic variation within Cyp2b9 and Ugt1a loci, respectively. These computational predictions were experimentally confirmed using expressed recombinant enzymes. The genetic changes affecting irinotecan metabolism in mice mirrored those in humans that are known to affect the pharmacokinetics and incidence of adverse responses to this medication.

View details for DOI 10.1073/pnas.0700724104

View details for Web of Science ID 000250897600036

View details for PubMedID 17978195

View details for PubMedCentralID PMC2077071