title: Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction.
abstract: Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Nishimura
authors.forename: Toshiko
authors.initials: T
authors.lastname: Nishimura
authors.forename: Yajing
authors.initials: Y
authors.lastname: Hu
authors.forename: Manhong
authors.initials: M
authors.lastname: Wu
authors.forename: Edward
authors.initials: E
authors.lastname: Pham
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.forename: Menashe
authors.initials: M
authors.lastname: Elazar
authors.forename: Michael
authors.initials: M
authors.lastname: Liu
authors.forename: Ramazan
authors.initials: R
authors.lastname: Idilman
authors.forename: Cihan
authors.initials: C
authors.lastname: Yurdaydin
authors.forename: Peter
authors.initials: P
authors.lastname: Angus
authors.forename: Catherine
authors.initials: C
authors.lastname: Stedman
authors.forename: Brian
authors.initials: B
authors.lastname: Murphy
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Glenn
authors.forename: Masato
authors.initials: M
authors.lastname: Nakamura
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Nomura
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: William L
authors.initials: WL
authors.lastname: Fitch
authors.forename: Gary
authors.initials: G
authors.lastname: Peltz
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001562:Benzimidazoles / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy / Q000201:enzymology / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011237:Predictive Value of Tests; D051381:Rats; D019438:Ritonavir / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D013045:Species Specificity; D018183:Transplantation Chimera / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019438:Ritonavir; C084582:clemizole