Investigating the effect of fluoxetine on the stereo selective pharmacokinetics of fexofenadine in parturients using in vivo and ex vivo placental transfer models

P-glycoprotein (P-gp) has an important role in the absorption, distribution and elimination of drugs that are its substrates (1). Fexofenadine is used to treat seasonal allergic rhinitis and chronic urticaria during pregnancy (2). Fexofenadine is also commonly used as a probe drug to assess the activity of P-gp in vivo. It should be noted that fexofenadine is marketed as a racemic mixture, and that (S)-(–)-fexofenadine has a greater affinity for P-gp than (R)-(+)-fexofenadine (3). Fluoxetine is a chiral drug used to treat depression during pregnancy, and previous in vitro studies have shown that fluoxetine is a potent inhibitor of human P-gp (4). The aims of our study were to assess the effect of fluoxetine on the stereo selective pharmacokinetics of fexofenadine in parturients and to examine the placental transfer of fexofenadine in vivo and using an ex vivo placental transfer model. Eight healthy term pregnant women received a single oral dose of 60 mg fexofenadine (racemic) 2-3 h before delivery (Control group) and another group of eight parturients received 40 mg fluoxetine (racemic) 3 h before receiving 60 mg fexofenadine (Interaction group). Serial blood and urine samples were collected for 48 h following fexofenadine administration. Maternal and umbilical cord blood samples were collected at delivery in order to evaluate placental drug transfer. The placental transfer of fexofenadine enantiomers was also assessed in 4 term placentae using the ex vivo dual perfusion of an isolated human placental cotyledon. Enantiomers for fexofenadine, fluoxetine and norfluoxetine were measured using liquid chromatography–tandem mass spectrometry. The drug concentrations were compared using Mann-Whitney and Wilcox on tests. In the Control group, the pharmacokinetics of fexofenadine were stereo selective with higher AUC0-∞ (423 vs. 268 ng.h/mL) and lower Vd/F (621 vs. 890 L), oral clearance (CL/F) (66.20 vs. 105.05 L/h) and renal clearance (CLR/F) (5.25 vs. 8.78 L/h) for (R)-(+)-fexofenadine than (S)-(-)-fexofenadine. There was limited placental transfer of both fexofenadine enantiomers, as determined by a fetal-to-maternal (F:M) ratios of 0.16. The (R)-(+)-to-(S)-(-) [R:S] ratio in the maternal vein was not significantly different than that in the umbilical vein (1.7 vs. 1.8), indicating that there was no chiral specificity by placental P-gp. Fluoxetine administration significantly increased AUC0-∞ (376 vs. 268 ng.h/mL) and reduced both CL/F (74.37 vs. 105.05 L/h) and CLR (3.50 vs. 8.78 L/h) only for the (S)-(-)-fexofenadine eutomer, as compared to the Control group. Fluoxetine did not alter umbilical vein/maternal vein ratios and fetal and maternal R:S ratios. Fexofenadine enantiomers had slow and limited placental transfer in the placental perfusion as characterized by F:M ratios of 0.18. R:S ratios were 1.0 (for both maternal and fetal compartments), which further confirms that placental P-gp does not exhibit chiral specificity. Fluoxetine did not change the rate of placental transfer, and the F:M and R:S ratios in maternal and fetal reservoirs. The results of the ex vivo placental perfusion model and the in vivo placental transfer were similar of both fexofenadine enantiomers, as shown by similar F:M ratios. This further supports the notion that the ex vivo model may be able to reliably predict placental drug transfer in vivo. Although fluoxetine stereo selectively inhibits intestinal P-gp, our study concluded that fluoxetine does not inhibit placental P-gp. This study indicates that the stereo selective pharmacokinetics of fexofenadine in parturients is primarily mediated by intestinal P-gp transport, and this stereo selectivity is altered by fluoxetine, a P-gp inhibitor.

(1) Montanari F and Ecker G F (2015). Adv Drug Deliv Rev 86: 17-26.

(2) So M et al. (2010). Can Fam Physician 56: 427-429.

(3) Miura M and Uno T (2010). Expert Opin Drug Metab Toxicol 6: 69-74.

(4) Weiss J et al. (2003). J Pharmacol Exp Ther 305: 197-204.