title: In vitro selective inhibition of human UDP-glucuronosyltransferase (UGT) 1A4 by finasteride, and prediction of in vivo drug-drug interactions.
abstract: In the present study, we evaluated the inhibitory potentials of finasteride for the major human hepatic UDP-glucuronosyltransferases (UGTs) (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15) in vitro using LC-MS/MS by specific marker reactions in human liver microsomes (except for UGT2B15) or recombinant supersomes (UGT2B15). Of the seven tested UGTs, finasteride potently, selectively, and competitively inhibited UGT1A4-mediated trifluoperazine-N-glucuronidation in human liver microsomes with an IC₅₀ value of 11.5 ± 1.78 μM and Ki value of 6.03 ± 0.291 μM. This inhibitory potency was similar to that of hecogenin, a well-known inhibitor of UGT1A4. However, finasteride did not seem to inhibit any of the other six UGTs: UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7, or UGT2B15. Similarly, finasteride markedly inhibited UGT1A4 activity in recombinant human UGT1A4 supersomes, with a Ki value of 6.05 ± 0.410 μM. In addition, finasteride strongly inhibited UGT1A4-catalyzed imipramine-N-β-D-glucuronidation. However, on the basis of an in vitro-in vivo extrapolation, our data strongly suggested that finasteride is unlikely to cause clinically significant drug-drug interactions mediated via inhibition of the hepatic UGT enzymes involved in drug metabolism in vivo.
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 420-743, Republic of Korea.
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 420-743, Republic of Korea.
authors.forename: Jung Bae
authors.initials: JB
authors.lastname: Park
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 420-743, Republic of Korea.
authors.forename: Doyun
authors.initials: D
authors.lastname: Kim
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 420-743, Republic of Korea.
authors.forename: Soo Hyeon
authors.initials: SH
authors.lastname: Bae
authors.affiliation: College of Pharmacy and BK21 PLUS R-FIND Team, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang, Gyeonggi-do 410-820, Republic of Korea.
authors.forename: Young-Won
authors.initials: YW
authors.lastname: Chin
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 420-743, Republic of Korea.
authors.forename: Euichaul
authors.initials: E
authors.lastname: Oh
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 420-743, Republic of Korea. Electronic address: baesk@catholic.ac.kr.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Bae
mesh_terms: D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011994:Recombinant Proteins / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; C019787:bilirubin glucuronoside glucuronosyltransferase; D018120:Finasteride; D014453:Glucuronosyltransferase
keywords: Finasteride; In vitro; In vivo prediction; UGT inhibition