title: Prediction of in vivo hepatic clearance and half-life of drug candidates in human using chimeric mice with humanized liver.
abstract: Accurate prediction of pharmacokinetics (PK) parameters in humans from animal data is difficult for various reasons, including species differences. However, chimeric mice with humanized liver (PXB mice; urokinase-type plasminogen activator/severe combined immunodeficiency mice repopulated with approximately 80% human hepatocytes) have been developed. The expression levels and metabolic activities of cytochrome P450 (P450) and non-P450 enzymes in the livers of PXB mice are similar to those in humans. In this study, we examined the predictability for human PK parameters from data obtained in PXB mice. Elimination of selected drugs involves multiple metabolic pathways mediated not only by P450 but also by non-P450 enzymes, such as UDP-glucuronosyltransferase, sulfotransferase, and aldehyde oxidase in liver. Direct comparison between in vitro intrinsic clearance (CL(int,in vitro)) in PXB mice hepatocytes and in vivo intrinsic clearance (CL(int,in vivo)) in humans, calculated based on a well stirred model, showed a moderate correlation (r² = 0.475, p = 0.009). However, when CL(int,in vivo) values in humans and PXB mice were compared similarly, there was a good correlation (r² = 0.754, p = 1.174 × 10⁻⁴). Elimination half-life (t(1/2)) after intravenous administration also showed a good correlation (r² = 0.886, p = 1.506 × 10⁻⁴) between humans and PXB mice. The rank order of CL and t(1/2) in human could be predicted at least, although it may not be possible to predict absolute values due to rather large prediction errors. Our results indicate that in vitro and in vivo experiments with PXB mice should be useful at least for semiquantitative prediction of the PK characteristics of candidate drugs in humans.
authors: Graduate School of Biomedical Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553 Japan. sanoh@hiroshima-u.ac.jp
authors: Seigo
authors: S
authors: Sanoh
authors: Aya
authors: A
authors: Horiguchi
authors: Kazumi
authors: K
authors: Sugihara
authors: Yaichiro
authors: Y
authors: Kotake
authors: Yoshitaka
authors: Y
authors: Tayama
authors: Hiroki
authors: H
authors: Ohshita
authors: Chise
authors: C
authors: Tateno
authors: Toru
authors: T
authors: Horie
authors: Shigeyuki
authors: S
authors: Kitamura
authors: Shigeru
authors: S
authors: Ohta
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002675:Child, Preschool; D002678:Chimera; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015507:Drugs, Investigational / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D018189:Immunomagnetic Separation; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000378:metabolism; D013045:Species Specificity; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: D015507:Drugs, Investigational; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D014568:Urokinase-Type Plasminogen Activator