and 257 ؎ 84 M, respectively, suggesting that FEX could not be used as a specific inhibitor for OATP1B1 and OATP1B3, although FEX was preferentially accepted by OATP1B3. In conclusion, this is, to our knowledge, the first demonstration that OATP1B3 is thought to be a major transporter involved in hepatic uptake of FEX in humans.Several members of different uptake transporter families are thought to be involved in the hepatic uptake of substances in human liver. Since the uptake of substances from blood into hepatocytes is the first step in the hepatocellular elimination, it is increasingly recognized that uptake transporters in the basolateral membrane play an important role in substrate disposition. Organic anion-transporting polypeptides (OATPs) form a superfamily of the sodium-independent transport system that mediates the transmembrane transport of a wide range of amphiphilic organic compounds including bile salts, organic dyes, steroid conjugates, thyroid hormones, anionic oligopeptides, and many drugs, such as pravastatin (Hagenbuch and Meier, 2004).Fexofenadine hydrochloride (FEX) (Aventis Pharmaceuticals, Inc., Kansas City, MO), a selective histamine H 1 -receptor antagonist, is clinically effective in the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria, for which it is considered as first-line therapy (Markham and Wagstaff, 1998;Simpson and Jarvis, 2000). FEX is the active metabolite of terfenadine (Seldane) and FEX showed no significant effect on the prolongation of the corrected QT interval (QT c ) in contrast to terfenadine (Pratt et al., 1999). After oral administration of [ 14 C]FEX (60 mg), most of the total dose was recovered in the urine (12%) and feces (80%), with the majority of the dose (Ͼ85%) recovered as the unchanged form (Lippert et al., 1996). This shows that metabolism is an insignificant elimination route and that FEX is poorly absorbed and/or is mainly eliminated from the liver into bile in its unchanged form.Hepatic metabolism is of minimal importance in the elimination of FEX. On the other hand, coadministration of erythromycin (500 mg three times a day) or ketoconazole (400 mg once daily) with FEX resulted in substantial increase in steady-state plasma concentration of FEX and its plasma AUC by 109 and 164%, respectively (product information, Aventis Pharmaceuticals, Inc.). However, a regional perfusion study showed that ketoconazole did not have a significant effect on the in vivo intestinal absorption of FEX when coadministered or given as a pretreatment (Tannergren et al., 2003).FEX was shown to be a substrate of P-glycoprotein and OATP1A2 (OATP-A), and its disposition was altered in mdr1a (Ϫ/Ϫ) mice (Cvetkovic et al., 1999). In addition, rifampin increased the oral clearance of FEX, suggesting an up-regulation of P-glycoprotein and, possibly, other transport processes (Hamman et al., 2001). Currently, several OATP family transporters such as OATP1B1 (OATP2/OATP-C), OATP1B3 (OATP8), and OATP2B1 (OATP-B) have been identified on the basal membrane of human...

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