Skip to main content

Advertisement

SpringerLink
Log in

P-gp is involved in the intestinal absorption and biliary excretion of afatinib in vitro and in rats

  • Original article
  • Published:
Pharmacological Reports Aims and scope Submit manuscript

Abstract

Background

Afatinib is an irreversible multi-targeted TKI, used in the treatment with EGFR mutated non-small cell lung cancer (NSCLC). The purpose of this study is to explore the molecular pharmacokinetic mechanism underlying the effect of P-gp inhibitors on the intestinal absorption and biliary excretion and to understand how P-gp inhibitors affect afatinib pharmacokinetics.

Methods

Pharmacokinetics in vivo, in situ intestinal perfusion, perfused rat liver in situ, Caco-2 cells, P-gp ATPase activity, sandwich-cultured rat hepatocytes (SCRH) and transfected-cell transport were used in the evaluation.

Results

P-gp inhibitor verapamil (Ver) markedly increased the plasma concentrations and significantly decreased the biliary excretion of afatinib in vivo. Ver increased the intestinal absorption and decreased biliary excretion of afatinib in situ single-pass intestinal perfusion studies and in situ perfused rat liver, respectively. The accumulation of afatinib in Caco-2 cells was enhanced by Ver and Cyclosporin A (CsA). The biliary excretion index (BEI) of afatinib in SCRH was decreased by Ver and CsA, respectively. The net efflux ratio of afatinib was 2.3 across vector-/MDR1–MDCKII cell monolayers and was decreased by P-gp inhibitor. The activity of P-gp ATPase was induced by afatinib and the Km and Vmax were 1.05 μM and 59.88 nmol ATP/mg hP-gp/min, respectively.

Conclusion

At least partly P-gp is involved in increasing the intestinal absorption and decreasing the biliary excretion of afatinib in rats.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AUC:

area under the plasma concentration-time curve

BEI:

biliary excretion index

CsA:

cyclosporin A

DDI:

drug–drug interaction

LC–MS/MS:

liquid chromatography–tandem mass spectrometry

MDCKII cells:

Madin–Darby canine kidney strain II cells

NER:

net efflux ratios

P-gp:

P-glycoprotein

SCRH:

sandwich-cultured rat hepatocytes

Ver:

verapamil hydrochloride

References

  1. Rowland M, Peck C, Tucker G. Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol. 2011;51:45–73.

    Article  CAS  Google Scholar 

  2. Konig J, Muller F, Fromm MF. Transporters and drug-drug interactions: important determinants of drug disposition and effects. Pharmacol Rev 2013;65:944–66.

    Article  Google Scholar 

  3. Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A 1987;84:265–9.

    Article  CAS  Google Scholar 

  4. Suzuki H, Sugiyama Y. Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. Eur J Pharm Sci 2000;12:3–12.

    Article  CAS  Google Scholar 

  5. Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol 2013;61:2495–502.

    Article  CAS  Google Scholar 

  6. Zhao W, Uehera S, Tanaka K, Tadokoro S, Kusamori K, Katsumi H, et al. Effects of polyoxyethylene alkyl ethers on the intestinal transport and absorption of rhodamine 123: a P-glycoprotein substrate by in vitro and In vivo studies. J Pharm Sci 2016;105:1526–34.

    Article  CAS  Google Scholar 

  7. Mohamed LA, Kaddoumi A. Tacrine sinusoidal uptake and biliary excretion in sandwich-cultured primary rat hepatocytes. J Pharm Sci 2014;17:427–38.

    Google Scholar 

  8. Gramatte T, Oertel R. Intestinal secretion of intravenous talinolol is inhibited by luminal R-verapamil. Clin Pharmacol Ther 1999;66:239–45.

    Article  CAS  Google Scholar 

  9. Bansal T, Mishra G, Jaggi M, Khar RK, Talegaonkar S. Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats. Eur J Pharm Sci 2009;36:580–90.

    Article  CAS  Google Scholar 

  10. Dungo RT, Keating GM. Afatinib: first global approval. Drugs 2013;73:1503–15.

    Article  CAS  Google Scholar 

  11. Burtness B, Bourhis JP, Vermorken JB, Harrington KJ, Cohen EE. Afatinib versus placebo as adjuvant therapy after chemoradiation in a double-blind, phase III study (LUX-Head & Neck 2) in patients with primary unresected, clinically intermediate-to-high-risk head and neck cancer: study protocol for a randomized controlled trial. Trials 2014;15:469.

    Article  Google Scholar 

  12. Chung CH, Rudek MA, Kang H, Marur S, John P, Tsottles N, et al. A phase I study afatinib/carboplatin/paclitaxel induction chemotherapy followed by standard chemoradiation in HPV-negative or high-risk HPV-positive locally advanced stage III/IVa/IVb head and neck squamous cell carcinoma. Oral Oncol 2016;53:54–9.

    Article  CAS  Google Scholar 

  13. Zhang J, Wang C, Liu Q, Meng Q, Cang J, Sun H, et al. Pharmacokinetic interaction between JBP485 and cephalexin in rats. Drug Metab Dispos 2010;38:930–8.

    Article  CAS  Google Scholar 

  14. Liu Z, Wang C, Liu Q, Meng Q, Cang J, Mei L, et al. Uptake, transport and regulation of JBP485 by PEPT1 in vitro and in vivo. Peptides 2011;32:747–54.

    Article  CAS  Google Scholar 

  15. Meng Q, Liu Q, Wang C, Sun H, Kaku T, Kato Y, et al. Molecular mechanisms of biliary excretion of cefditoren and the effects of cefditoren on the expression levels of hepatic transporters. Drug Metab Pharmacokinet 2010;25:320–7.

    Article  CAS  Google Scholar 

  16. LeCluyse EL, Bullock PL, Parkinson A, Hochman JH. Cultured rat hepatocytes. Pharm Biotechnol 1996;8:121–59.

    Article  CAS  Google Scholar 

  17. Zhu Y, Meng Q, Wang C, Liu Q, Sun H, Kaku T, et al. Organic anion transporters involved in the excretion of bestatin in the kidney. Peptides 2012;33:265–71.

    Article  CAS  Google Scholar 

  18. Wolking S, Schaeffeler E, Lerche H, Schwab M, Nies AT. Impact of genetic polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on drug disposition and potential clinical implications: update of the literature. Clin Pharmacokinet 2015;54:709–35.

    Article  CAS  Google Scholar 

  19. Peters S, Zimmermann S, Adjei AA. Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions. Cancer Treat Rev 2014;40:917–26.

    Article  CAS  Google Scholar 

  20. Bedada SK, Yellu NR, Neerati P. Effect of resveratrol on the pharmacokinetics of fexofenadine in rats: involvement of P-glycoprotein inhibition. Pharmacol Rep 2016;68:338–43.

    Article  CAS  Google Scholar 

  21. Kathawala RJ, Gupta P, Ashby Jr. CR, Chen ZS. The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. Drug Resist Updat 2015;18:1–17.

    Article  Google Scholar 

  22. Harwood MD, Neuhoff S, Carlson GL, Warhurst G, Rostami-Hodjegan A. Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro-in vivo extrapolation of oral drug absorption. Biopharm Drug Dispos 2013;34:2–28.

    Article  CAS  Google Scholar 

  23. Wang L, Wang C, Liu Q, Meng Q, Huo X, Sun P, et al. PEPT1- and OAT1/3-mediated drug-drug interactions between bestatin and cefixime in vivo and in vitro in rats, and in vitro in human. Eur J Pharm Sci 2014;63:77–86.

    Article  CAS  Google Scholar 

  24. Xu DH, Yan M, Li HD, Fang PF, Liu YW. Influence of P-glycoprotein on brucine transport at the in vitro blood-brain barrier. Eur J Pharmacol 2012;690:68–76.

    Article  CAS  Google Scholar 

  25. Gianni L, Vigano L, Locatelli A, Capri G, Giani A, Tarenzi E, et al. Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol 1997;15:1906–15.

    Article  CAS  Google Scholar 

  26. Kunimatsu S, Mizuno T, Fukudo M, Katsura T. Effect of P-glycoprotein and breast cancer resistance protein inhibition on the pharmacokinetics of sunitinib in rats. Drug Metab Dispos 2013;41:1592–7.

    Article  CAS  Google Scholar 

  27. Schnell D, Buschke S, Fuchs H, Gansser D, Goeldner RG, Uttenreuther-Fischer M, et al. Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment. Cancer Chemother Pharmacol 2014;74:267–75.

    Article  CAS  Google Scholar 

  28. Swift B, Pfeifer ND, Brouwer KL. Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity. Drug Metab Rev 2010;42:446–71.

    Article  CAS  Google Scholar 

  29. Li L, Yao QQ, Xu SY, Hu HH, Shen Q, Tian Y, et al. Cyclosporin A affects the bioavailability of ginkgolic acids via inhibition of P-gp and BCRP. Eur J Pharm Biopharm 2014;88:759–67.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China

    Yan Zhang, Changyuan Wang, Zhihao Liu, Qiang Meng, Xiaokui Huo, Qi Liu, Pengyuan Sun, Xiaobo Yang, Huijun Sun, Xiaodong Ma & Kexin Liu

  2. Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China

    Changyuan Wang, Zhihao Liu, Qiang Meng, Xiaokui Huo, Qi Liu, Pengyuan Sun, Xiaobo Yang, Huijun Sun, Xiaodong Ma & Kexin Liu

  3. Peking University Third Hospital Yanqing Hospital, Beijing, China

    Yan Zhang

Authors
  1. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Changyuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhihao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiang Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaokui Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pengyuan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaobo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Huijun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaodong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kexin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kexin Liu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Wang, C., Liu, Z. et al. P-gp is involved in the intestinal absorption and biliary excretion of afatinib in vitro and in rats. Pharmacol. Rep 70, 243–250 (2018). https://doi.org/10.1016/j.pharep.2017.10.005

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1016/j.pharep.2017.10.005

Keywords

Search

Navigation