1α,25‐Dihydroxyvitamin D₃ on intestinal transporter function: studies with the rat everted intestinal sac

Abstract

Previous studies have shown that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment (2.56 nmol/kg i.p. daily×4) increased PepT1, Mrp2, Mrp4, Asbt, but not Mdr1/P-gp in the rat small intestine. In this study, the intestinal everted sac technique, together with various select probes: mannitol (paracellular transport), glycylsarcosine (PepT1), 5(and 6)-carboxy-2',7'-dichlorofluorescein (CDF) diacetate (precursor of CDF for Mrp2), adefovir dipivoxil (precursor of adefovir for Mrp4) and digoxin (P-gp) was used to examine the functional changes of these transporters. After establishing identical permeabilities (Papp) of mannitol for the apical-to-basolateral (A-to-B) and basolateral-to-apical (B-to-A) directions at 20 min in 1,25(OH)2D3-treated vs. vehicle-treated duodenal, jejunal and ileal everted sacs, a significant enhancement of net A-to-B transport of glycylsarcosine in the duodenum, increased B-to-A transport of CDF and A-to-B and B-to-A transport of adefovir in the jejunum were observed with 1,25(OH)2 D3 treatment. However, the A-to-B and B-to-A transport of digoxin in the ileum was unchanged. These changes in transporter function in the rat intestinal everted sac corresponded well to changes in proteins that were observed previously. This study confirms that the rat intestinal PepT1, Mrp2 and Mrp4, but not P-gp are functionally induced by 1,25(OH)2D3 treatment via the vitamin D receptor (VDR).

Effects of 1α,25-Dihydroxyvitamin D₃ on Intestinal Absorption and Disposition of Adefovir Dipivoxil and Its Metabolite, Adefovir, in Rats

“…Then, the intracellularly generated adefovir is absorbed into the blood by crossing the basolateral membrane of enterocytes primarily via MRP4/Mrp4-mediated efflux rather than by passive diffusion, due to the highly negative charge of adefovir. 13,15,17) Consistent with this, our previous in vitro study using everted Since adefovir dipivoxil is a substrate of P-gp, and its intestinal permeation can be limited by P-gp-mediated efflux, 30) we could not rule out the regulation of P-gp function by 1,25(OH) 2 D 3 treatment. However, when the effects of 1,25(OH) 2 D 3 on the intestinal absorption of adefovir dipivoxil in rat duodenum, jejunum and ileum segments were observed using the in situ closed loop technique (Fig.…”

“…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(OH) 2 D 3 on transporter substrate drug pharmacokinetics in animals or humans.…”

“…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(OH) 2 D 3 on transporter substrate drug pharmacokinetics in animals or humans.…”

“…Adefovir, an acyclic nucleoside phosphonate analogue with antiviral activity, acts as an inhibitor of reverse transcriptase, 16) and is a well-recognized MRP4/Mrp4 substrate. 13,15,17,18) Since the oral absorption of adefovir is quite poor due to its negative charge on phosphonate groups, its prodrug, adefovir dipivoxil, is synthesized to mask the negative charge, enhancing membrane permeability and oral bioavailability. 19) The prodrug, adefovir dipivoxil, is also recognized as a P-gp substrate.…”

TheSLCO1A2Gene, Encoding Human Organic Anion-Transporting Polypeptide 1A2, Is Transactivated by the Vitamin D Receptor

“…It was reported that a number of genes encoding intestinal membrane transporters for both endogenous substances and drugs and xenobiotics are regulated by vitamin D 3 and VDR Fan et al, 2009;Tachibana et al, 2009;Chow et al, 2010;Maeng et al, 2011). We have investigated whether vitamin D 3 and VDR regulate the expression of the SLCO1A2 gene, which encodes an important membrane transporter for intestinal absorption of numerous drugs.…”