title: Metabolic pathways of the camptothecin analog AR-67.
abstract: 7-tert-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67; also known as DB-67) is a novel lipophilic camptothecin analog in early-phase anticancer clinical trials. In support of these studies, we evaluated the metabolism of AR-67 in vitro and identified potential metabolites in patient samples. The lactone form of AR-67 was found to be preferentially metabolized over AR-67 carboxylate in human microsomes. Subsequently, the lactone form was tested as a substrate in a panel of CYP450 and UDP-glucuronosyltransferase (UGT) enzymes known to metabolize the majority of clinically approved molecules. AR-67 was metabolized by CYP3A5, CYP3A4, CYP1A1, and CYP1A2, in order of activity. Extrahepatic UGT1A8 and UGT1A7 possessed at least 6-fold higher metabolizing activity than UGT1A1 and other UGT enzymes tested. CYP1A1 and UGT1A7 displayed Michaelis-Menten kinetics, whereas CYP3A4, CYP3A5, and UGT1A8 displayed kinetics consistent with substrate inhibition. Chromatographic analysis of representative patient plasma and urine samples demonstrated the presence of AR-67 glucuronides and oxidized products in the urine but only in very minimal amounts. We conclude that limited in vivo metabolism of AR-67 by UGT1A1 may partly explain the absence of AR-67 glucuronides in plasma and hypothesize that UGT1A8- and CYP3A-mediated biotransformation within the gastrointestinal epithelium may provide protective mechanisms against AR-67 gastrointestinal toxicity.
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Horn
authors.forename: Marta
authors.initials: M
authors.lastname: Milewska
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Arnold
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000652:urine; D017321:Clinical Trials, Phase I as Topic; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007783:Lactones / Q000032:analysis* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D017646:Organosilicon Compounds / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D010084:Oxidation-Reduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D007783:Lactones; D017646:Organosilicon Compounds; C415575:7-tert-butyldimethylsilyl-10-hydroxycamptothecin; D003577:Cytochrome P-450 Enzyme System; D002166:Camptothecin