Factors affecting the in vivo lactone stability and systemic clearance of the lipophilic camptothecin analogue AR-67.
OBJECTIVE
The narrow efficacy-toxicity window of anticancer agents necessitates understanding of factors contributing to their disposition. This is especially true for camptothecins as they exist in the lactone and carboxylate forms with each moiety differentially interacting with efflux or uptake transporters. Here we determined the disposition of the lactone and carboxylate forms of AR-67, a 3(rd) generation camptothecin analogue.


METHODS
Pharmacokinetic studies were conducted in rats given intravenous boluses of AR-67 lactone or carboxylate with or without pharmacologic inhibitor pretreatment (GF120918 or rifampin). Pharmacokinetic modeling was used to estimate clearances, while simulations assessed the impact of clearance changes on overall AR-67 exposure.


RESULTS
Our modeling showed that carboxylate clearance was 3.5-fold higher than that of the lactone. GF120918 decreased lactone clearance only, but rifampin decreased both lactone and carboxylate clearances. Simulations showed that decreasing carboxylate clearance, which controls the overall drug disposition, leads to significant increase in AR-67 exposure.


CONCLUSIONS
The apparent in vivo blood stability of AR-67 is partly dependent on the increased carboxylate clearance. This may have clinical implications for populations with single nucleotide polymorphisms that impair the function of uptake transporter genes (e.g., SLCO1B1), which are potentially responsible for AR-67 carboxylate clearance.
Adane
Eyob D
ED
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
Liu
Zhiwei
Z
Xiang
Tian-Xiang
TX
Anderson
Bradley D
BD
Leggas
Markos
M
D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005260:Female; D007783:Lactones / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D008954:Models, Biological; D015394:Molecular Structure; D017646:Organosilicon Compounds / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007783:Lactones; D017646:Organosilicon Compounds; C415575:7-tert-butyldimethylsilyl-10-hydroxycamptothecin; D002166:Camptothecin