PT  - JOURNAL ARTICLE
AU  - Hiroyuki Kusuhara
AU  - Masatomo Miura
AU  - Norio Yasui-Furukori
AU  - Kenta Yoshida
AU  - Yumiko Akamine
AU  - Miyu Yokochi
AU  - Shinya Fukizawa
AU  - Kazuaki Ikejiri
AU  - Kayoko Kanamitsu
AU  - Tsukasa Uno
AU  - Yuichi Sugiyama
TI  - Effect of Coadministration of Single and Multiple Doses of Rifampicin on the Pharmacokinetics of Fexofenadine Enantiomers in Healthy Subjects
AID  - 10.1124/dmd.112.048330
DP  - 2013 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 206--213
VI  - 41
IP  - 1
4099  - http://dmd.aspetjournals.org/content/41/1/206.short
4100  - http://dmd.aspetjournals.org/content/41/1/206.full
SO  - Drug Metab Dispos2013 Jan 01; 41
AB  - The effect of rifampicin on the pharmacokinetics of fexofenadine enantiomers was examined in healthy subjects who received fexofenadine alone or with single or multiple doses of rifampicin (600 mg). A single coadministered dose of rifampicin significantly decreased the oral clearance (CLtot/F) and renal clearance (CLr) of S- and R-fexofenadine by 76 and 62%, and 73 and 62%, respectively. Even after multiple doses, rifampicin significantly decreased these parameters, although the effect on the CLtot/F was slightly blunted. Multiple doses of rifampicin abolished the difference in the CLtot/F of fexofenadine enantiomers, whereas the stereoselectivity in the CLr persisted. Rifampicin inhibited the uptake of fexofenadine enantiomers by human hepatocytes via organic anion transporter (OAT) OATP1B3 and its basal-to-apical transport in Caco-2 cells, but not OAT3-mediated or multidrug and toxic compound extrusion 1 (MATE1)–mediated transport. The plasma-unbound fraction of S-fexofenadine was 1.8 times higher than that of R-fexofenadine. The rifampicin-sensitive uptake by hepatocytes was 1.6 times higher for R-fexofenadine, whereas the transport activities by OATP1B3, OAT3, MATE1, or P-glycoprotein were identical for both enantiomers. S-fexofenadine is a more potent human histamine H1 receptor antagonist than R-fexofenadine. In conclusion, rifampicin has multiple interaction sites with fexofenadine, all of which contribute to increasing the area under the curve of fexofenadine when they are given simultaneously, to surpass the effect of the induction of P-glycoprotein elicited by multiple doses.