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Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents

Title
Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents
Authors
Lee, JaeokKang, JiyeonKwon, Na-YunSivaraman, AneeshNaik, RaviJin, So-YoungOh, A. ReumShin, Jae-HoNa, YounghwaLee, KyeongLee, Hwa-Jeong
Ewha Authors
이화정이재옥
SCOPUS Author ID
이화정scopus; 이재옥scopus
Issue Date
2021
Journal Title
PHARMACEUTICS
ISSN
1999-4923JCR Link
Citation
PHARMACEUTICS vol. 13, no. 4
Keywords
P-gp and BCRP dual inhibitiontopotecanexcipientoral bioavailabilitypharmacokineticstumor growth
Publisher
MDPI
Indexed
SCIE; SCOPUS WOS
Document Type
Article
Abstract
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 derived 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 alterations in body weight. Moreover, we investigated the effects of an oral drug formulation (Cremophor(R) EL, Tween(R) 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 (C-max) and the area under the plasma concentration-time curve from zero to infinity (AUC(INF)) (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.
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DOI
10.3390/pharmaceutics13040559
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약학대학 > 약학과 > Journal papers
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