A simple in vitro model to study the stability of acylglucuronides.
BACKGROUND
Compounds containing the carboxylic functional group (e.g. non-steroidal anti-inflammatory drugs) can be metabolized to form acylglucuronides. Acylglucuronides are intrinsically reactive metabolites capable of undergoing hydrolysis, intra-molecular rearrangement, and formation of covalent adducts with proteins, which may generate potential toxicity. The purpose of this study is to develop an in vitro screening model to assess degradation kinetics of acylglucuronides.


METHODS
Zomepirac, ibuprofen, gemfibrozil, and compounds A, B, C, and D were incubated in the presence of rat microsomal protein and uridine 5'-diphosphoglucuronic acid (UDPGA), followed by addition of human plasma to evaluate degradation kinetics of the acylglucuronides. As a comparison, authentic acylglucuronide standards of zomepirac, ibuprofen, gemfibrozil, and compounds A, B, C, and D were chemically synthesized and were evaluated for degradation kinetics.


RESULTS
The results demonstrate that degradation half-life values of acylglucuronides of zomepirac, ibuprofen, gemfibrozil, and compounds A, B, C, and D determined by the in vitro formation/degradation model were in the same rank-order with those of the authentic acylglucuronide standards.


CONCLUSIONS
For the seven compounds tested, the model placed the stability of the acylglucuronides formed in vitro in a rank-order consistent with authentic acylglucuronide standards. The method allows for a rapid assessment of the stability of acylglucuronides.
Chen
Zhesheng
Z
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. zhesheng_chen@merck.com
Holt
Tom G
TG
Pivnichny
James V
JV
Leung
Kwan
K
D000818:Animals; D004355:Drug Stability; D015248:Gemfibrozil / Q000134:cerebrospinal fluid; D020719:Glucuronides / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007052:Ibuprofen / Q000134:cerebrospinal fluid; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008956:Models, Chemical; D051381:Rats; D014046:Tolmetin / Q000031:analogs & derivatives / Q000737:chemistry; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D020719:Glucuronides; D014535:Uridine Diphosphate Glucuronic Acid; C020549:zomepirac; D014046:Tolmetin; D015248:Gemfibrozil; D007052:Ibuprofen