文章基本信息

标题：Effects of 1α,25-Dihydroxyvitamin D₃ on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats
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作者：In-Soo Yoon ; Jun-Hyeng Son ; Sang-Bum Kim 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2015
卷号：38
期号：11
页码：1732-1737
DOI：10.1248/bpb.b15-00356
出版社：The Pharmaceutical Society of Japan
摘要：The aim of this study was to investigate the effect of 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), an active form of vitamin D, on the oral absorption and disposition of adefovir dipivoxil (P-glycoprotein (P-gp) substrate) and its major active metabolite, adefovir (multidrug resistance-associated protein 4 (Mrp4) substrate), in rats. The pharmacokinetics of intravenous adefovir and oral adefovir dipivoxil was evaluated in control and 1,25(OH)₂D₃-treated rats. The intestinal absorption of adefovir dipivoxil was investigated through an in situ closed loop study, and the tissue distribution of adefovir after oral administration of adefovir dipivoxil was evaluated in the two groups. There was no significant difference in pharmacokinetic parameters of intravenous adefovir between the two groups. Importantly, the total area under the plasma concentration–time curve from time zero to time infinity ( AUC ), peak plasma concentration ( C _max) and extent of absolute oral bioavailability ( F ) of adefovir after oral administration of adefovir dipivoxil were significantly higher in 1,25(OH)₂D₃-treated rats than in control rats. In the in situ closed loop study, there was no significant difference in the remaining fraction of adefovir dipivoxil in the duodenum, jejunum and ileum loops between the two groups. In the tissue distribution study after oral administration of adefovir dipivoxil, the tissue-to-plasma partition coefficients of adefovir in the liver, brain, kidney, and intestine were significantly lower in the 1,25(OH)₂D₃-treated rats than in control rats. The present study indicates that 1,25(OH)₂D₃ treatment can enhance the oral absorption of adefovir dipivoxil, likely via the induction of basolateral Mrp4 function in rat intestine. However, the impact of 1,25(OH)₂D₃ treatment on the pharmacokinetics of intravenous adefovir was limited. These results could lead to further studies in clinically significant P-gp and/or MRP4-mediated 1,25(OH)₂D₃–drug interactions.