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 plasmaunbound 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.

The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion

“…In addition, AJ significantly decreases the uptake of both enantiomers into oocytes injected with OATP2B1 cRNA [31]. Furthermore, we have shown that the uptake of both enantiomers is the same in P-gp-, OATP1B3-, OAT3-, and multidrug and toxic compound extrusion 1 (MATE1)-expressing cells [30]. Thus, these results suggest that OATP2B1 may be the main factor mediating the stereoselectivity of fexofenadine and fexofenadine enantiomer pharmacokinetics.…”

“…Although Robbins et al reported that the two enantiomers are pharmacologically identical [23], our recent in vitro binding assays demonstrated that (S)-fexofenadine is a more potent human histamine H1 receptor antagonist than (R)-fexofenadine [30]. Therefore, (S)-fexofenadine shows larger receptor occupancy and consequently makes a greater contribution to the pharmacological response than (R)-fexofenadine.…”

“…In contrast, our recent report indicated that polymorphisms in the SLCO gene, which encodes OATP, are more highly associated with the pharmacokinetics of fexofenadine enantiomers than polymorphisms in the ABCB1 gene (also known as MDR1), which encodes P-gp [28]. In addition, rifampicin is a potent P-gp inducer and OATP inhibitor and has been shown to cause a marked increase in the concentrations of both enantiomers of fexofenadine [29,30]. These results suggested that rifampicin may inhibit the OATP-mediated transport of both enantiomers in the liver, and this effect may be greater than the induction effect on P-gp.…”

Mass Spectrometry-Based Targeted Proteomics as a Tool to Elucidate the Expression and Function of Intestinal Drug Transporters

“…Considering the nearly parallel expression pattern of ABCB1 and PXR along the intestine (own unpublished mRNA data), it is not surprising that co-administration of prototypic enzyme/transporter inducers such as rifampicin or St. John's wort results in substantial DDIs (3,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The same is true for inhibition of ABCB1 for example by macrolide antibiotics (Table I).…”

“…1). Thus, co-administration of inducers or inhibitors and substrates of these proteins were shown to cause clinically relevant drugdrug interactions (DDIs , Table I) (3,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Moreover, several uptake carriers from the SLC transporter family have been reported to mediate the intestinal uptake of many endogenous compounds (e.g.…”