title: Effect of coadministration of single and multiple doses of rifampicin on the pharmacokinetics of fexofenadine enantiomers in healthy subjects.
abstract: 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 (CL(tot)/F) and renal clearance (CL(r)) 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 CL(tot)/F was slightly blunted. Multiple doses of rifampicin abolished the difference in the CL(tot)/F of fexofenadine enantiomers, whereas the stereoselectivity in the CL(r) 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.
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
authors.forename: Norio
authors.initials: N
authors.lastname: Yasui-Furukori
authors.forename: Kenta
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Akamine
authors.forename: Miyu
authors.initials: M
authors.lastname: Yokochi
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukizawa
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Ikejiri
authors.forename: Kayoko
authors.initials: K
authors.lastname: Kanamitsu
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Uno
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D039563:Histamine H1 Antagonists, Non-Sedating / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D012016:Reference Values; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D039563:Histamine H1 Antagonists, Non-Sedating; D029362:Organic Anion Transporters, Sodium-Independent; D027701:Organic Cation Transport Proteins; C521869:SLC47A1 protein, human; C114338:organic anion transport protein 3; D016593:Terfenadine; C093230:fexofenadine; D012293:Rifampin