Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmacokinetics

Abstract

Background and Objective

Fluoxetine, antidepressant widely-used during pregnancy, is a selective inhibitor for P-glycoprotein (P-gp). Fexofenadine, an in vivo P-gp probe, is an antihistamine drug for seasonal allergic rhinitis and chronic urticaria treatment during pregnancy and it is available as a racemic mixture. This study evaluated the chiral discrimination of P-gp investigating the effect of fluoxetine on maternal-fetal pharmacokinetics of fexofenadine.

Methods

Healthy parturient women received either a single oral dose of 60 mg racemic fexofenadine (Control group; n = 8) or a single oral dose of 40 mg racemic fluoxetine 3 h before a single oral dose of 60 mg racemic fexofenadine (Interaction group; n = 8). Maternal blood and urine samples were collected up to 48 h after fexofenadine administration. At delivery, maternal-placental-fetal blood samples were collected.

Results

The maternal pharmacokinetics of fexofenadine was enantioselective (AUC0–∞R-(+)/S-(−) ~ 1.5) in both control and interaction groups. Fluoxetine increased AUC0-∞ (267.7 vs 376.1 ng.h/mL) and decreased oral total clearance (105.1 vs 74.4 L/h) only of S-(−)-fexofenadine, whereas the renal clearance were reduced for both enantiomers, suggesting that the intestinal P-gp-mediated transport of S-(−)-fexofenadine is influenced by fluoxetine to a greater extent that the R-(+)-fexofenadine. However, the transplacental transfer of fexofenadine is low (~16%), non-enantioselective and non-influenced by fluoxetine.

Conclusions

A single oral dose of 40 mg fluoxetine inhibited the intestinal P-gp mediated transport of S-(−)-fexofenadine to a greater extent than R-(+)-fexofenadine in parturient women. However, the placental P-gp did not discriminate fexofenadine enantiomers and was not inhibited by fluoxetine.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T. Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol. 2005;106:1071–83.

    Article  Google Scholar 

  2. 2.

    Field T. Prenatal anxiety effects: a review. Infant Behav Dev. 2017;49:120–8.

    Article  Google Scholar 

  3. 3.

    Alwan S, Friedman JM, Chambers C. Safety of selective serotonin reuptake inhibitors in pregnancy: a review of current evidence. CNS Drugs. 2016;30:495–515.

    Article  Google Scholar 

  4. 4.

    Cooper WO, Willy ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol. 2007;196:544.e1–5.

    Article  Google Scholar 

  5. 5.

    DeVane CL. Metabolism and pharmacokinetics of selective serotonin reuptake inhibitors. Cell Mol Neurobiol. 1999;19:443–66.

    CAS  Article  Google Scholar 

  6. 6.

    McConathy J, Owens MJ. Stereochemistry in drug action. Prim Care Companion J Clin Psychiatry. 2003;5:70–3.

    Article  Google Scholar 

  7. 7.

    DeVane CL, Boulton DW. Great expectations in stereochemistry: focus on antidepressants. CNS Spectr. 2002;5:28–33.

    Article  Google Scholar 

  8. 8.

    Wong DT, Fuller RW, Robertson DW. Fluoxetine and its two enantiomers as selective serotonin uptake inhibitors. Acta Pharm Nord. 1990;2:171–80.

    CAS  PubMed  Google Scholar 

  9. 9.

    Fuller RW, Snoddy HD, Krushinski JH, Robertson DW. Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo. Neuropharmacology. 1992;31:997–1000.

    CAS  Article  Google Scholar 

  10. 10.

    Carvalho DM, Filgueira GCO, Marques MP, Caris JA, Duarte G, Cavalli RC, et al. Analysis of fluoxetine and norfluoxetine enantiomers in human plasma and amniotic fluid by LC-MS/MS and its application to clinical pharmacokinetics in pregnant women. J Res Anal. 2017;3:15–23.

    Google Scholar 

  11. 11.

    Weiss J, Dormann S-MG, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther. 2003;305:197–204.

    CAS  Article  Google Scholar 

  12. 12.

    Argov M, Kashi R, Peer D, Margalit R. Treatment of resistant human colon cancer xenografts by a fluoxetine–doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimen. Cancer Lett. 2009;274:118–25.

    CAS  Article  Google Scholar 

  13. 13.

    Schrickx JA, Fink-Gremmels J. Inhibition of P-glycoprotein by psychotherapeutic drugs in a canine cell model. J Vet Pharmacol Therap. 2014;37:515–7.

    CAS  Article  Google Scholar 

  14. 14.

    Peer D, Dekel Y, Melikhov D, Margalit R. Fluoxetine inhibits multidrug resistance extrusion pumps and enhances responses to chemotherapy in syngeneic and in human xenograft mouse tumor models. Cancer Res. 2004;64:7562–9.

    CAS  Article  Google Scholar 

  15. 15.

    Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, et al. Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug−drug interactions. J Med Chem. 2012;55:4740–63.

    CAS  Article  Google Scholar 

  16. 16.

    Robbins DK, Castles MA, Pack DJ, Bhargava VO, Weir SJ. Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers. Biopharm Drug Dispos. 1998;19:455–63.

    CAS  Article  Google Scholar 

  17. 17.

    Kusuhara H, Miura M, Yasui-Furukori N, Yoshida K, Akamine Y, Yokochi M, et al. Effect of coadministration of single and multiple doses of rifampicin on the pharmacokinetics of fexofenadine enantiomers in healthy subjects. Drug Metab Dispos. 2013;41:206–13.

    CAS  Article  Google Scholar 

  18. 18.

    Miura M, Uno T, Tateishi T, Suzuki T. Pharmacokinetics of fexofenadine enantiomers in healthy subjects. Chirality. 2007;19:223–7.

    CAS  Article  Google Scholar 

  19. 19.

    Gundogdu E, Alvarez IG, Karasulu E. Improvement of effect of water-in-oil microemulsion as an oral delivery system for fexofenadine: in vitro and in vivo studies. Int J Nanomedicine. 2011;6:1631–40.

    CAS  Article  Google Scholar 

  20. 20.

    Wu CY, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/ elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22:11–23.

    CAS  Article  Google Scholar 

  21. 21.

    Miura M, Uno T. Clinical pharmacokinetics of fexofenadine enantiomers. Expert Opin Drug Metab Toxicol. 2010;6:69–74.

    CAS  Article  Google Scholar 

  22. 22.

    Cvetkovic M, Leake B, Fromm MF, Wilkinson GR, Kim RB. OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos. 1999;27:866–71.

    CAS  PubMed  Google Scholar 

  23. 23.

    Akamine Y, Miura M. An update on the clinical pharmacokinetics of fexofenadine enantiomers. Expert Opin Drug Metab Toxicol. 2018;14:429–34.

    CAS  Article  Google Scholar 

  24. 24.

    Akamine Y, Miura M, Yasui-Furukori MK, Uno T. Carbamazepine differentially affects the pharmacokinetics of fexofenadine enantiomers. Br J Clin Pharmacol. 2011;73:478–81.

    Article  Google Scholar 

  25. 25.

    Akamine Y, Miura M, Komori H, Tamai I, Ieiri I, Yasui-Furukori N, et al. The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion. Drug Metab Pharmacokinet. 2015;30:352–7.

    CAS  Article  Google Scholar 

  26. 26.

    Akamine Y, Miura M, Komori H, Saito S, Kusuhara H, Tamai I, et al. Effects of one-time apple juice ingestion on the pharmacokinetics of fexofenadine enantiomers. Eur J Clin Pharmacol. 2014;70:1087–95.

    CAS  Article  Google Scholar 

  27. 27.

    Akamine Y, Miura M, Sunagawa S, Kagaya H, Yasui-Furukori N, Uno T. Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers. Xenobiotica. 2010;40:782–9.

    CAS  Article  Google Scholar 

  28. 28.

    Akamine Y, Miura M, Yasui-Furukori MK, Ieiri I, Uno T. Effects of multiple-dose rifampicin 450 mg on the pharmacokinetics of fexofenadine enantiomers in Japanese volunteers. J Clin Pharm Therap. 2015;40:98–103.

    CAS  Article  Google Scholar 

  29. 29.

    Sakugawa T, Miura M, Hokama N, Suzuki T, Tateishi T, Uno T. Enantioselective disposition of fexofenadine with the P-glycoprotein inhibitor verapamil. Br J Clin Pharmacol. 2009;67:535–40.

    CAS  Article  Google Scholar 

  30. 30.

    Tateishi T, Miura M, Suzuki T, Uno T. The different effects of itraconazole on the pharmacokinetics of fexofenadine enantiomers. Br J Clin Pharmacol. 2008;65:693–700.

    CAS  Article  Google Scholar 

  31. 31.

    Togami K, Tosaki Y, Chono S, Morimoto K, Hayasaka M, Tada H. Enantioselective uptake of fexofenadine by Caco-2 cells as model intestinal ephitelial cells. J Pharm Pharmacol. 2012;65:22–9.

    Article  Google Scholar 

  32. 32.

    Sanofi-Aventis. ALLEGRA™, fexofenadine hydrochloride: U.S. prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20786se8-014,20872se8-011,20625se8-012_allegra_lbl.pdf. Accessed 5 Apr 2020.

  33. 33.

    Pinto LSR, Vale GT, Moreira FL, Marques MP, Coelho EB, Cavalli RC, et al. Direct chiral LC-MS/MS analysis of fexofenadine enantiomers in plasma and urine with application in a maternal-fetal pharmacokinetic study. J Chrom B. 2020; 145:122094.

  34. 34.

    Li F, Howard KD, Myers MJ. Influence of P-glycoprotein on the disposition of fexofenadine and its enantiomers. J Pharm Pharmacol. 2017;69:274–84.

    CAS  Article  Google Scholar 

  35. 35.

    Tasnif Y, Morado J, Hebert MF. Pregnancy-related pharmacokinetic changes. Clin Pharmacol Ther. 2016;100:53–61.

    CAS  Article  Google Scholar 

  36. 36.

    Koren G, Ornoy A. The role of the placenta in drug transport and fetal drug exposure. Exp Rev Clin Pharmacol. 2018;11:373–85.

    CAS  Article  Google Scholar 

  37. 37.

    Hebert MF, Easterling TR, Kirby B, Carr DB, Buchanan ML, Rutherford T, et al. Effects of pregnancy on CYP3A and P-glycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington Specialized Center of research study. Clin Pharmacol Ther. 2008;84:248–53.

    CAS  Article  Google Scholar 

  38. 38.

    Tahara H, Kusuhara H, Fuse E, Sugiyama Y. P-glycoprotein plays a major role in the efflux of fexofenadine in the small intestine and blood-brain barrier, but only a limited role in its biliary excretion. Drug Metab Dispos. 2005;33:963–8.

    CAS  Article  Google Scholar 

  39. 39.

    Yasui-Furukori N, Uno T, Sugawara K, Tateishi T. Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics. Clin Pharmacol Ther. 2005;77:17–23.

    CAS  Article  Google Scholar 

  40. 40.

    Al-Enazy S, Ali S, Albekairi N, El-Tawil M, Rytting E. Placental control of drug delivery. Adv Drug Deliv Rev. 2017;116:63–72.

    CAS  Article  Google Scholar 

  41. 41.

    Joshi AA, Vaidya SS, St-Pierre MV, Mikheev AM, Desino KE, Nyandege AN, et al. Placental ABC transporters: biological impact and pharmaceutical significance. Pharm Res. 2016;33:2847–78.

    CAS  Article  Google Scholar 

  42. 42.

    Mathias AA, Hitti J, Unadkat JD. P-glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages. Am J Physiol Regul Integr Comp Physiol. 2005;289:R963–9.

    CAS  Article  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

The authors thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for financial support. The authors declare no conflict of interest. Informed consent was obtained from all individual participants included in the study.

Funding

This study was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Vera Lucia Lanchote.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key points

• P-glycoprotein (P-gp) is a drug transporter expressed in several organs, including intestine and placenta, and it is crucial in the enantioselective pharmacokinetics of fexofenadine. Then, the P-gp inhibitor fluoxetine could affect the maternal-fetal pharmacokinetics of fexofenadine enantiomers.

• The specific P-gp inhibitor fluoxetine affected the intestinal P-gp mediated transport of S-(−)-fexofenadine to a greater extent than R-(+)-fexofenadine in parturient women. However, the placental P-gp did not discriminate fexofenadine enantiomers and was not inhibited by fluoxetine.

• This study contributes with the evaluation of the efficacy and safety of fexofenadine enantiomers administered during pregnancy and shows that enantioselective pharmacokinetics should be evaluated for other drugs substrates of P-gp during gestation, considering that fluoxetine is a common antidepressant used during pregnancy.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pinto, L., Moreira, F.d., Nardotto, G.H.B. et al. Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmacokinetics. Pharm Res 37, 131 (2020). https://doi.org/10.1007/s11095-020-02854-4

Download citation

KEY WORDS

  • CPKA-D-20-00095
  • fexofenadine
  • fluoxetine
  • pregnancy
  • pharmacokinetics
  • P-gp