TY - JOUR T1 - A Humanized <em>UGT1</em> Mouse Model Expressing the <em>UGT1A1</em>*<em>28</em> Allele for Assessing Drug Clearance by UGT1A1-Dependent Glucuronidation JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 879 LP - 886 DO - 10.1124/dmd.109.030130 VL - 38 IS - 5 AU - Hongliang Cai AU - Nghia Nguyen AU - Vincent Peterkin AU - Young-Sun Yang AU - Kathy Hotz AU - Deirdre Beaton La Placa AU - Shujuan Chen AU - Robert H. Tukey AU - Jeffrey C. Stevens Y1 - 2010/05/01 UR - http://dmd.aspetjournals.org/content/38/5/879.abstract N2 - 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 (Km and Vmax) 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(UGT1A1*28) Ugt1(−/−) mice]. The well characterized substrate for UGT1A1, 7-ethyl-10-hydroxy-camptothecin (SN-38), showed the greatest difference in parent drug exposure (∼3-fold increase) and clearance (∼3-fold decrease) in Tg(UGT1A1*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, 5α-epoxy-3, 14-dihydroxymorphinan-6-one (naloxone) was not altered in Tg(UGT1A1*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; Merck &amp; Co., 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(UGT1A1*28) Ugt1(−/−) mice showed patterns consistent with the in vivo pharmacokinetic data. For SN-38 glucuronidation, Vmax decreased 5-fold in Tg(UGT1A1*28) Ugt1(−/−) mouse liver microsomes compared with microsomes prepared from wild-type mice, and decreased 10-fold compared with phenobarbital-treated Tg(UGT1A1*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 Vmax were minimal. Thus, Tg(UGT1A1*28) Ugt1(−/−) mice can serve as a pharmacokinetic model to further investigate the effects of UGT1A1 expression on drug metabolism. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -