Open AccessEffects of breast cancer resistance protein inhibitors and pharmaceutical excipients on decreasing gastrointestinal toxicity of camptothecin analogs 1
Author(s) -
ZHANG Xinxin,
PAN Weisan,
GAN Li,
ZHU Chunliu,
GAN Yong
Publication year - 2008
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2008.00883.x
Subject(s) - abcg2 , pharmacology , toxicity , camptothecin , excretion , irinotecan , chemistry , topotecan , medicine , atp binding cassette transporter , cancer , transporter , chemotherapy , colorectal cancer , biochemistry , gene
Aim: To investigate the effect of breast cancer resistance protein (BCRP) inhibitors and pharmaceutical excipients on reducing the biliary excretion of camptothecins (CPT), ameliorating delayed‐type diarrhea and intestinal mucosa damage induced by CPT. Methods: The cumulative biliary excretion of irinotecan (CPT‐11) and hydroxycamptothecin (HCPT) with or without BCRP inhibitors and excipients was investigated in rats. The gastrointestinal toxicity, assessed as the diarrheal score, body weight change and microscopic pathological damage was also determined in rats. Results: Breast cancer resistance protein (BCRP) exhibited important effects on the biliary excretion of CPT. Coadministration of BCRP inhibitors such as GF120918 and cyclosporin A reduced the biliary excretion of CPT‐11 and HCPT. Pharmaceutical excipients such as Pluronic F68 and PEG 2000 stearate also showed inhibitory effects on BCRP and similarly reduced CPT biliary excretion. The observed gastrointestinal toxicity was ameliorated by coadministration of BCRP inhibitors and excipients compared with injection of CPT‐11 and HCPT alone. Conclusion: The use of excipients as inhibitors of BCRP is safe and relatively non‐toxic, and may lead to important pharmacotherapeutic benefits by decreasing the gastrointestinal toxicity of CPT.