Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents
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 can...
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MDPI AG
2021-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/4/559 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jaeok Lee |
| collection | DOAJ |
| description | 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<sup>®</sup> EL, Tween<sup>®</sup> 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<sub>max</sub>) and the area under the plasma concentration–time curve from zero to infinity (AUC<sub>INF</sub>) (<i>p</i><i><</i> 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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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T12:17:07Z |
| publishDate | 2021-04-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-3038fe5315bd40aab778612323b0af6b2023-11-21T15:45:31ZengMDPI AGPharmaceutics1999-49232021-04-0113455910.3390/pharmaceutics13040559Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in RodentsJaeok Lee0Jiyeon Kang1Na-Yun Kwon2Aneesh Sivaraman3Ravi Naik4So-Young Jin5A. Reum Oh6Jae-Ho Shin7Younghwa Na8Kyeong Lee9Hwa-Jeong Lee10College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, KoreaCollege of Pharmacy, Dongguk University, Goyang-si 10326, KoreaCollege of Pharmacy, Dongguk University, Goyang-si 10326, KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, KoreaCollege of Pharmacy, CHA University, Pocheon-si 11160, KoreaCollege of Pharmacy, CHA University, Pocheon-si 11160, KoreaCollege of Pharmacy, Dongguk University, Goyang-si 10326, KoreaCollege of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, KoreaP-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<sup>®</sup> EL, Tween<sup>®</sup> 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<sub>max</sub>) and the area under the plasma concentration–time curve from zero to infinity (AUC<sub>INF</sub>) (<i>p</i><i><</i> 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.https://www.mdpi.com/1999-4923/13/4/559P-gp and BCRP dual inhibitiontopotecanexcipientoral bioavailabilitypharmacokineticstumor growth |
| spellingShingle | 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 Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents Pharmaceutics P-gp and BCRP dual inhibition topotecan excipient oral bioavailability pharmacokinetics tumor growth |
| title | Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents |
| title_full | Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents |
| title_fullStr | Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents |
| title_full_unstemmed | Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents |
| title_short | Dual Inhibition of P-gp and BCRP Improves Oral Topotecan Bioavailability in Rodents |
| title_sort | dual inhibition of p gp and bcrp improves oral topotecan bioavailability in rodents |
| topic | P-gp and BCRP dual inhibition topotecan excipient oral bioavailability pharmacokinetics tumor growth |
| url | https://www.mdpi.com/1999-4923/13/4/559 |
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