RT Journal Article
SR Electronic
T1 Effect of Coadministration of Single and Multiple Doses of Rifampicin on the Pharmacokinetics of Fexofenadine Enantiomers in Healthy Subjects
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 206
OP 213
DO 10.1124/dmd.112.048330
VO 41
IS 1
A1 Hiroyuki Kusuhara
A1 Masatomo Miura
A1 Norio Yasui-Furukori
A1 Kenta Yoshida
A1 Yumiko Akamine
A1 Miyu Yokochi
A1 Shinya Fukizawa
A1 Kazuaki Ikejiri
A1 Kayoko Kanamitsu
A1 Tsukasa Uno
A1 Yuichi Sugiyama
YR 2013
UL http://dmd.aspetjournals.org/content/41/1/206.abstract
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.