Involvement of P-glycoprotein, multidrug resistance protein 2 and breast cancer resistance protein in the transport of belotecan and topotecan in Caco-2 and MDCKII cells.
OBJECTIVE
To investigate the underlying mechanism of low bioavailabilities of the water-soluble camptothecin derivatives, belotecan and topotecan.


METHODS
The bioavailability of belotecan and topotecan in rats was determined following oral administration of each drug at a dose of 5 mg/kg body weight. The vectorial transport of each drug was measured in Caco-2 and engineered MDCK II cells.


RESULTS
The bioavailability of belotecan (11.4%) and topotecan (32.0%) in rats was increased to 61.5% and 40.8%, respectively, by the preadministration of CsA at a dose of 40 mg/kg. Contrary to the absorptive transport, the secretory transport of these drugs across the Caco-2 cell monolayer was concentration-dependent, saturable, and significantly inhibited by the cis presence of verapamil (a P-gp substrate), MK-571 (an MRP inhibitor), bromosulfophthalein (BSP, an MRP2 inhibitor), fumitremorgin C (FTC, a BCRP inhibitor) and cyclosporine A (CsA, an inhibitor of P-gp and BCRP, and a substrate of P-gp) suggesting the involvement of these transporters, which could be further confirmed in MDCKII/P-gp, MDCKII/MRP2 and MDCKII/BCRP cells.


CONCLUSIONS
The involvement of secretory transporters P-gp, MRP2 and BCRP, particularly for belotecan, as well as a low passive permeability, appears to be responsible for the low bioavailability of belotecan and topotecan.
Li
Hong
H
National Research Laboratory for Transporters Targeted Drug Design, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 599 Gwanangno, Gwanak-gu, Seoul 151-742, Republic of Korea.
Jin
Hyo-Eon
HE
Kim
Wooyoung
W
Han
Yong-Hae
YH
Kim
Dae-Duk
DD
Chung
Suk-Jae
SJ
Shim
Chang-Koo
CK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004285:Dogs; D006801:Humans; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019772:Topotecan / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002166:Camptothecin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D019772:Topotecan; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C489249:Abcg2 protein, rat; C116963:belotecan