An update on the clinical pharmacokinetics of fexofenadine enantiomers

ABSTRACT

Introduction: Fexofenadine is administered as a racemic mixture of (R)- and (S)-enantiomers. The plasma concentrations of (R)-fexofenadine in humans are about 1.5-fold higher than those of the (S)-enantiomer. Such differences in the pharmacokinetics between fexofenadine enantiomers are likely to be dependent on stereoselectivity for affinity to drug-transporters.

Areas covered: This review focuses on elucidation of differences in clinical pharmacokinetics between fexofenadine enantiomers.

Expert opinion: Differences in pharmacokinetics between fexofenadine enantiomers were caused by organic anion transporting polypeptide (OATP) 2B1, with a minor contribution from P-glycoprotein (P-gp). In vitro studies using OATP2B1 cRNA showed that (R)-fexofenadine uptake into oocytes is greater than (S)-enantiomer uptake. P-gp inducers, carbamazepine, and inhibitors such as itraconazole and verapamil show greater effects on the pharmacokinetics of (S)-fexofenadine. Apple juice and grape fruit juice, OATP2B1 inhibitors, significantly decrease the exposure of both fexofenadine enantiomers, particularly the (S)-enantiomer, but do not change the t_1/2. Rifampicin significantly increases plasma concentrations of both enantiomers through inhibition of OATP1B3, whereas enantioselectivity of fexofenadine uptake by OATP1B3-expressing cells has not been observed. Combinations of multiple transporters such as OATP2B1 and P-gp facilitate enantioselective disposition of fexofenadine. Drug-transporters appear to be capable of chiral discrimination for transport of drugs with an asymmetric center.

KEYWORDS:

• Fexofenadine enantiomer
• organic anion transporting polypeptide
• P-glycoprotein
• pharmacokinetics
• stereoselectivity

Article highlights

• The plasma concentration of (R)-fexofenadine in humans is about 1.5-fold higher than that of the (S)-enantiomer.

• (S)-Fexofenadine is influenced by P-gp inducer/inhibitors and OATP inhibitors to a greater extent than the (R)-enantiomer in humans.

• The differences in pharmacokinetics between fexofenadine enantiomers are caused by mainly OATP2B1, with minor contributions from P-gp.

• Combinations of multiple transporters seem to provide enantioselective transport of fexofenadine.

• Drug-transporters are capable of chiral discrimination for the transport of drugs with an asymmetric center, and these results are expected to facilitate clinical studies.

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.