Intestinal glucuronidation metabolism may have a greater impact on oral bioavailability than hepatic glucuronidation metabolism in humans: a study with raloxifene, substrate for UGT1A1, 1A8, 1A9, and 1A10.
作者： Takashi Mizuma
DOI: 10.1016/J.IJPHARM.2009.05.044
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摘要: The kinetic impact of intestinal glucuronidation metabolism on oral bioavailability (F) was assessed using reported human data raloxifene, which only 2%. Kinetic analysis showed that presystemic availability (Fpg) 5.4%, whereas fraction absorbed (Ff) and hepatic (Fh) were 63% 59.3%, respectively. Thus, Fpg the lowest among factors, affect bioavailability. In addition, much lower than Fh, suggesting has a greater metabolism. It been UDP-glucuronosyltransferase (UGT) 1A1, UGT1A8, UGT1A9, UGT1A10 are enzymes for raloxifene glucuronidation, UGT1A8 absent in liver, UGT1A1, present intestine. Therefore, it is also suggested catalyzed by UGTs, particularly UGT1A10, may play important roles first-pass metabolism, causing low
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sci-hub.se 参考文章(8)
Brian Davies, Tim Morris, Physiological Parameters in Laboratory Animals and Humans Pharmaceutical Research. ,vol. 10, pp. 1093- 1095 ,(1993) , 10.1023/A:1018943613122
Takashi Mizuma, Assessment of presystemic and systemic intestinal availability of orally administered drugs using in vitro and in vivo data in humans: Intestinal sulfation metabolism impacts presystemic availability much more than systemic availability of salbutamol, SULT1A3 substrate Journal of Pharmaceutical Sciences. ,vol. 97, pp. 5471- 5476 ,(2008) , 10.1002/JPS.21363
Takashi Mizuma, Akira Tsuji, Masahiro Hayashi, Does the well-stirred model assess the intestinal first-pass effect well? Journal of Pharmacy and Pharmacology. ,vol. 56, pp. 1597- 1599 ,(2010) , 10.1211/0022357044850
Chi-Yuan Wu, Leslie Z. Benet, Mary F. Hebert, Suneel K. Gupta, Malcolm Rowland, Denise Y. Gomez, Vincent J. Wacher, Differentiation of absorption and first-pass gut and hepatic metabolism in humans: Studies with cyclosporine Clinical Pharmacology & Therapeutics. ,vol. 58, pp. 492- 497 ,(1995) , 10.1016/0009-9236(95)90168-X
Takashi Mizuma, Akihiro Koyanagi, Shoji Awazu, Intestinal transport and metabolism of glucose-conjugated kyotorphin and cyclic kyotorphin: metabolic degradation is crucial to intestinal absorption of peptide drugs Biochimica et Biophysica Acta. ,vol. 1475, pp. 90- 98 ,(2000) , 10.1016/S0304-4165(00)00051-9
Takashi Mizuma, Kinetic impact of presystemic intestinal metabolism on drug absorption: experiment and data analysis for the prediction of in vivo absorption from in vitro data. Drug Metabolism and Pharmacokinetics. ,vol. 17, pp. 496- 506 ,(2002) , 10.2133/DMPK.17.496
Robert H. Tukey, Christian P. Strassburg, Human UDP-Glucuronosyltransferases: Metabolism, Expression, and Disease Annual Review of Pharmacology and Toxicology. ,vol. 40, pp. 581- 616 ,(2000) , 10.1146/ANNUREV.PHARMTOX.40.1.581
Daniel C. Kemp, Peter W. Fan, Jeffrey C. Stevens, Characterization of raloxifene glucuronidation in vitro: contribution of intestinal metabolism to presystemic clearance. Drug Metabolism and Disposition. ,vol. 30, pp. 694- 700 ,(2002) , 10.1124/DMD.30.6.694