A Humanized UGT1 Mouse Model Expressing the UGT1A1*28 Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation
| Autor: | Hongliang Cai, Nghia Nguyen, Deirdre Beaton La Placa, Shujuan Chen, Vincent Peterkin, Robert H. Tukey, Kathy Hotz, Young Sun Yang, Jeffrey C. Stevens |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Glucuronosyltransferase Metabolic Clearance Rate Glucuronidation Gene Expression Pharmaceutical Science Mice Transgenic Biology Pharmacology Irinotecan digestive system Mice Glucuronic Acid Pharmacokinetics In vivo Animals Humans Dimethyl Sulfoxide Enzyme inducer Alleles Mice Knockout Naloxone Anticholesteremic Agents Articles Ezetimibe Antineoplastic Agents Phytogenic UGT2B7 Mice Inbred C57BL Kinetics Liver Pharmaceutical Preparations Area Under Curve Enzyme Induction Phenobarbital Models Animal UDP-Glucuronosyltransferase 1A9 Biocatalysis Microsomes Liver biology.protein Microsome Azetidines Camptothecin Drug metabolism |
| Zdroj: | Drug Metabolism and Disposition. 38:879-886 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | Humanized mice that express the human UDP-glucuronosyltransferase (UGT) 1 locus have been developed in a Ugt1-null background as a model to improve predictions of human UGT1A-dependent drug clearance. Enzyme kinetic parameters (K(m) and V(max)) and pharmacokinetic properties of three probe drugs were compared using wild-type and humanized UGT1 mice that express the Gilbert's UGT1A1*28 allele [Tg(UGT1(A1*28)) Ugt1(-/-) mice]. The well characterized substrate for UGT1A1, 7-ethyl-10-hydroxy-camptothecin (SN-38), showed the greatest difference in parent drug exposure ( approximately 3-fold increase) and clearance ( approximately 3-fold decrease) in Tg(UGT1(A1*28)) Ugt1(-/-) mice after intravenous administration compared with wild-type and phenobarbital-treated animals. In contrast, the clearance of the UGT2B7 substrate (-)-17-allyl-4, 5alpha-epoxy-3, 14-dihydroxymorphinan-6-one (naloxone) was not altered in Tg(UGT1(A1*28)) Ugt1(-/-) mice. In addition, pharmacokinetic parameters with 1-(4-fluorophenyl)3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone (ezetimibe, Zetia; MerckCo., Whitehouse Station, NJ), considered to be a major substrate for UGT1A1, showed small to no dependence on UGT1A1-directed glucuronidation. Enzyme kinetic parameters assessed for SN-38, ezetimibe, and naloxone using liver microsomes prepared from wild-type and Tg(UGT1(A1*28)) Ugt1(-/-) mice showed patterns consistent with the in vivo pharmacokinetic data. For SN-38 glucuronidation, V(max) decreased 5-fold in Tg(UGT1(A1*28)) Ugt1(-/-) mouse liver microsomes compared with microsomes prepared from wild-type mice, and decreased 10-fold compared with phenobarbital-treated Tg(UGT1(A1*28)) Ugt1(-/-) mice. These differences are consistent with SN-38 glucuronidation activities using HLMs isolated from individuals genotyped as UGT1A1*1 or UGT1A1*28. For ezetimibe and naloxone the differences in V(max) were minimal. Thus, Tg(UGT1(A1*28)) Ugt1(-/-) mice can serve as a pharmacokinetic model to further investigate the effects of UGT1A1 expression on drug metabolism. |
| Databáze: | OpenAIRE |
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