title: Effects of 1α,25-Dihydroxyvitamin D3 on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats.
abstract: 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 (Cmax) 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.
authors.affiliation: College of Pharmacy and Natural Medicine Research Institute, Mokpo National University.
authors.forename: In-Soo
authors.initials: IS
authors.lastname: Yoon
authors.forename: Jun-Hyeng
authors.initials: JH
authors.lastname: Son
authors.forename: Sang-Bum
authors.initials: SB
authors.lastname: Kim
authors.forename: Min-Koo
authors.initials: MK
authors.lastname: Choi
authors.forename: Han-Joo
authors.initials: HJ
authors.lastname: Maeng
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002117:Calcitriol / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D063065:Organophosphonates / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000225:Adenine; D002117:Calcitriol; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D063065:Organophosphonates; C489542:Abcc4 protein, rat; C053001:adefovir; C106812:adefovir dipivoxil