Regional absorption of fexofenadine in rat intestine.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
MacLean
Caroline
C
Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany. maclean@uni-hd.de
Moenning
Ulla
U
Reichel
Andreas
A
Fricker
Gert
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D003106:Colon / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology; D039563:Histamine H1 Antagonists, Non-Sedating / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D039563:Histamine H1 Antagonists, Non-Sedating; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; D016593:Terfenadine; C421143:Slco1a5 protein, rat; C533062:Slco2b1 protein, rat; C093230:fexofenadine; C070272:valspodar