In silico and in vitro pharmacogenetic analysis in mice

• DOI: 10.1073/pnas.0700724104
• Publication Date: 2007-11-01T01:17:43Z
• Authors: Yingying Guo; Peng Lu; Erin Farrell; Xun Zhang; Paul Weller; Mario Monshouwer; Jianmei Wang; Guochun Liao; Zhaomei Zhang; Steven Hu; John Allard; Steve Shafer; Jonathan Usuka; Gary Peltz
• Keywords: 0301 basic medicine; Recombinant Proteins; 3. Good health; Mice; 03 medical and health sciences; Cytochrome P-450 Enzyme System; Liver; Pharmaceutical Preparations; Pharmacogenetics; Steroid Hydroxylases; Animals; Testosterone; Aryl Hydrocarbon Hydroxylases; Glucuronosyltransferase; Cytochrome P450 Family 2; Biotransformation

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 16α-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.