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 D 3 (1,25(OH) 2 D 3 ), 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) 2 D 3 -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) 2 D 3 -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-toplasma partition coefficients of adefovir in the liver, brain, kidney, and intestine were significantly lower in 4) During the past decades, significant physiological roles of VDR in calcium and bone homeostasis have been well established. 5)However, it is increasingly recognized that VDR is also crucial in the regulation of drug transporters, and 1,25(OH) 2 D 3 can lead to VDR-mediated changes in target genes of drug transporters. [6][7][8][9][10] Since VDR is abundantly expressed in the intestine, 11) the effects of 1,25(OH) 2 D 3 (i.e., VDR activation) on the expression of intestinal drug transporters are frequently investigated. 1,25(OH) 2 D 3 increases the mRNA expression and function of multidrug resistance protein 1 (MDR1) in the human colorectal adenocarcinoma cell lines, LS174T and Caco-2 cells in vitro. 8,12) It also increases the protein expressions of multidrug resistance-associated protein 2 and 4 (MRP2 and MRP4) in Caco-2 cells. 8,13) In rats, 1,25(OH) 2 D 3 treatment in vivo increases the protein expressions of Mrp2, Mrp3, Mrp4, and the oligopeptide transporter 1 (PepT1) without altering the mRNA and protein expressions of Mdr1a (P-glycoprotein; P-gp). 14)Moreover, our previous studies using rat everted intestinal sac technique confirmed that the in vitro functions of rat intestinal Mrp2, Mrp4 and PepT1, but not P-gp are induced by 1,25(OH) 2 D 3 treatment via VDR activation. 15) However, changes in the expression and/or in vitro functions of drug transporters do not always correlate with the fates of therapeutic agents in the whole body system. Therefore, further studies are needed on the effects of 1,25(O...

Differential regulation of intestinal and hepatic CYP3A by 1α,25‐dihydroxyvitamin D3: Effects on in vivo oral absorption and disposition of buspirone in rats

“…The 1,25(OH) 2 D 3 solution was then diluted to 2.56 nmol/mL with a vehicle (filtered corn oil). Rats ( n = 5 in each group) were administered an intraperitoneal injection at a dose of 0 (vehicle) or 2.56 nmol/kg, daily for 4 consecutive days, as reported previously (Chow et al, , ; Kim et al, ; Maeng, Durk, Chow, Ghoneim, & Pang, ; Yoon et al, ).…”

“…Recently, we investigated the effect of 1,25(OH) 2 D 3 on the oral absorption and disposition of adefovir dipivoxil (a P‐gp substrate) and its major active metabolite, adefovir (an MRP4 substrate), in rats. The previous study first demonstrated that 1,25(OH) 2 D 3 treatment enhanced the oral absorption of adefovir dipivoxil and increased the systemic exposure of adefovir in vivo, likely via the induction of basolateral MRP4 expression in rat intestine (Yoon, Son, Kim, Choi, & Maeng, ).…”

Differential Effects of 1α,25-Dihydroxyvitamin D3 on the Expressions and Functions of Hepatic CYP and UGT Enzymes and Its Pharmacokinetic Consequences In Vivo

“…For example, the mRNA/protein expressions and activities of multidrug resistance-associated protein 4 (MRP4), P-glycoprotein (P-gp), cytochrome P450 3A4 (CYP3A4), and multidrug resistance-associated protein 2 (MRP2) in Caco-2 cells were increased by 1,25(OH) 2 D 3 treatment in vitro [9,10]. In terms of transporter-mediated drug-drug interactions (DDIs), 1,25(OH) 2 D 3 significantly reduced the renal clearances of cefdinir and cefadroxil by down-regulating organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) expressions in rat kidney [11], but enhanced the oral absorption of adefovir dipivoxil by inducing MRP4 in rat intestine [12]. In the mice treated with 1,25(OH) 2 D 3, the pharmacokinetics of digoxin, a P-gp probe drug, was significantly affected in vivo, resulting in increased total clearance and renal clearance via regulation of P-gp by VDR activation [13].…”

Pharmacokinetics studies of 4′-cyano-2′-deoxyguanosine, a potent inhibitor of the hepatitis B virus, in rats

“…Thus, CdG, as well as ETV, is thought to be absorbed in the upper small intestine, with the result that it is rapidly absorbed after oral administration. It should also be noted that when orally administered, CdG shows a good bioavailability (approximately 70% in rats) similar to other NAs (ETV: approximately 78% in rats, adefovir dipivoxil: approximately 50% in rats). These findings indicate that CdG has the necessary properties for use as an oral preparation, similar to other NAs for HBV treatment.…”