Species-dependent glucuronidation of drugs by immobilized rabbit, rhesus monkey, and human UDP-glucuronyltransferases.
The utility of immobilized microsomal enzymes from rabbit liver for the synthesis of a variety of conjugated drug metabolites has been demonstrated in our laboratory. Here, this capability is extended to microsomal preparations from monkey and human liver. A comparative study of glucuronidation of various substrates was carried out using immobilized uridine-5'-diphosphoglucuronyltransferase from rabbit, rhesus monkey, and human liver. The three drugs used for the study (sulfadimethoxine, oxazepam, and cyproheptadine) were chosen on the basis of their previously reported in vivo species differences in glucuronidation. Aglycons were incubated with UDP-glucuronic acid in the presence of immobilized UDP-glucuronyl-transferase at pH 7.4 for 16 hr at 37 degrees C. Glucuronide products were purified by high performance liquid chromatography and further characterized by thin layer chromatography and mass spectometry. Species-dependent glucuronidation was observed in all three cases. Differences in the in vitro product formation paralleled in vivo species differences for the three drugs studied. The same glucuronides were produced by immobilized human liver microsomes as have been found to be formed in vivo from the three drugs studied.
D000818:Animals; D003533:Cyproheptadine / Q000378:metabolism; D004800:Enzymes, Immobilized / Q000494:pharmacology*; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000494:pharmacology*; D008253:Macaca mulatta; D008862:Microsomes, Liver / Q000201:enzymology; D010076:Oxazepam / Q000378:metabolism; D011817:Rabbits; D013045:Species Specificity; D013412:Sulfadimethoxine / Q000378:metabolism
D004800:Enzymes, Immobilized; D005965:Glucuronates; D003533:Cyproheptadine; D013412:Sulfadimethoxine; D010076:Oxazepam; D014453:Glucuronosyltransferase