Dual inhibition of P-gp and BCRP improves oral topotecan bioavailability in rodents

Jaeok Lee, Jiyeon Kang, Na Yun Kwon, Aneesh Sivaraman, Ravi Naik, So Young Jin, A. Reum Oh, Jae Ho Shin, Younghwa Na, Kyeong Lee, Hwa Jeong Lee

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17 Scopus citations


P-glycoprotein (P-gp) inhibition has been studied to overcome multidrug resistance in cancer chemotherapy but failed in clinical trials due to low/toxic effects. Recently, a dual modulation of transporters and natural derivatives have been examined to surmount this limitation. We examined breast cancer resistance protein (BCRP) inhibition in vitro and in vivo by P-gp inhibitors de-rived from natural compounds in previous studies. P-gp inhibitors increased the accumulation of the anticancer drug, topotecan (TPT)—a substrate of P-gp and BCRP, albeit with higher affinity for BCRP—in BCRP-overexpressing cells, resulting in cell death. These dual inhibitors, when orally co-administered with TPT, enhanced TPT bioavailability with slightly reduced total oral clearance (Clt/F) in rats. In xenograft mice, they strengthened oral TPT-induced tumor reduction with no al-terations in body weight. Moreover, we investigated the effects of an oral drug formulation (Cre-mophor® EL, Tween® 80, and polyethylene glycol 400) on the transporters function. The excipients increased TPT accumulation in P-gp-or BCRP-overexpressing cells. Oral TPT bioavailability was higher with the formulation than with a control, as shown by the increases in the maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve from zero to infinity (AUCINF) (p < 0.01). Therefore, oral TPT bioavailability was enhanced by P-gp/BCRP dual inhibition, which resulted in a formulation-mediated increase in absorption and decrease in elimination, and a dual inhibitor-mediated decrease in elimination. These results suggest that the combination of dual inhibition by a natural derivative and the drug formulation can be a useful clinical approach.

Original languageEnglish
Article number559
Issue number4
StatePublished - Apr 2021

Bibliographical note

Funding Information:
Funding: This research work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (2020R1A2B5B01002489 (H.J.L.) and 2018R1A5A2023127 (K.L.)). J.L. was supported by a Research Professor Grant 2021 of Ewha Womans University.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Excipient
  • Oral bioavailability
  • P-gp and BCRP dual inhibition
  • Pharmacokinetics
  • Topotecan
  • Tumor growth


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