sdz-psc-833 and fexofenadine

Expression of Pgp along the GI-tract of rats increases towards distal segments. We assessed the in vivo relevance by determining the absorption of fexofenadine from proximal and distal parts of rat intestine. Since it has been reported that fexofenadine is also actively taken up by OATP/oatps, we quantified rat oatp1a5 and oatp2b1 mRNA in gut mucosa to elucidate a possible contribution of an oatp-mediated active uptake of fexofenadine.. Absorption was determined after drug administration into ligated segments of rat duodenum/upper jejunum and terminal ileum, respectively, in the absence and the presence of the Pgp blocker PSC-833s. Portal vein blood was sampled. Expression of Pgp in the mucosa of proximal and distal intestinal segments was analyzed by Western Blot. Oatp1a5 and oatp2b1 mRNA in intestinal mucosa was quantified by real-time qRT-PCR.. Portal vein AUC(0-90min) of fexofenadine was significantly higher after absorption from proximal segments compared to distal segments. Accordingly, Pgp expression was significantly lower in proximal compared to distal segments. Inhibition of Pgp by PSC-833 affected fexofenadine absorption only in distal segments resulting in AUC values comparable to the proximal data. Both oatp1a5 and oatp2b1 mRNA expression increased along the small intestine.. The study demonstrates that Pgp is responsible for a limitation of fexofenadine absorption from distal small intestine. These findings are supported by the found pattern of expression for oatp1a5 and oatp2b1, showing that an active oatp-mediated uptake plays no role for fexofenadine absorption in rats.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Colon; Cyclosporins; Histamine H1 Antagonists, Non-Sedating; Humans; Intestinal Absorption; Intestinal Mucosa; Intestine, Small; Male; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Rats; Rats, Wistar; RNA, Messenger; Terfenadine

Fexofenadine, a nonsedating antihistamine, does not undergo significant metabolic biotransformation. Accordingly, it was hypothesized that uptake and efflux transporters could be importantly involved in the drug's disposition. Utilizing a recombinant vaccinia expression system, members of the organic anion transporting polypeptide family, such as the human organic anion transporting polypeptide (OATP) and rat organic anion transporting polypeptides 1 and 2 (Oatp1 and Oatp2), were found to mediate [(14)C]fexofenadine cellular uptake. On the other hand, the bile acid transporter human sodium taurocholate cotransporting polypeptide (NTCP) and the rat organic cation transporter rOCT1 did not exhibit such activity. P-glycoprotein (P-gp) was identified as a fexofenadine efflux transporter, using the LLC-PK1 cell, a polarized epithelial cell line lacking P-gp, and the derivative cell line (L-MDR1), which overexpresses P-gp. In addition, oral and i.v. administration of [(14)C]fexofenadine to mice lacking mdr1a-encoded P-gp resulted in 5- and 9-fold increases in the drug's plasma and brain levels, respectively, compared with wild-type mice. Also, a number of drug inhibitors of P-gp were found to be effective inhibitors of OATP. Because OATP transporters and P-gp colocalize in organs of importance to drug disposition such as the liver, their activity provides an explanation for the heretofore unknown mechanism(s) responsible for fexofenadine's disposition and suggests potentially similar roles in the disposition of other xenobiotics.

Topics: Animals; Anion Transport Proteins; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport, Active; Caco-2 Cells; Carrier Proteins; Genes, MDR; HeLa Cells; Histamine H1 Antagonists; Humans; LLC-PK1 Cells; Mice; Rats; Swine; Terfenadine; Tissue Distribution; Transfection; Vaccinia virus