Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents
- 주제(키워드) P-gp and BCRP dual inhibition , topotecan , excipient , oral bioavailability , pharmacokinetics , tumor growth
- 주제(기타) Pharmacology & Pharmacy
- 설명문(일반) [Lee, Jaeok; Kang, Jiyeon; Kwon, Na-Yun; Jin, So-Young; Oh, A. Reum; Lee, Hwa-Jeong] Ewha Womans Univ, Coll Pharm, Seoul 03760, South Korea; [Lee, Jaeok; Kang, Jiyeon; Kwon, Na-Yun; Jin, So-Young; Oh, A. Reum; Lee, Hwa-Jeong] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Sivaraman, Aneesh; Naik, Ravi; Lee, Kyeong] Dongguk Univ, Coll Pharm, Goyang Si 10326, South Korea; [Shin, Jae-Ho; Na, Younghwa] CHA Univ, Coll Pharm, Pocheon Si 11160, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 MDPI
- 발행년도 2021
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000181563
- 본문언어 영어
- Published As http://dx.doi.org/10.3390/pharmaceutics13040559
초록/요약
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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