Abstract

Dopamine D-1 receptor antagonists are currently under investigation for use as antipsychotic agents. Two potent and selective D-1 receptor antagonists, SCH 39166 and SCH 23390, have been studied extensively in various experimental animal models. SCH 39166 has a more prolonged duration of action in primates in vivo and a lower rate of in vitro glucuronidation by microsomes from squirrel monkey liver. Because the rate of glucuronidation seems to govern the duration of action and may limit the use of these agents in humans, the glucuronidation of SCH 39166 and SCH 23390 by microsomes isolated from human liver was studied. The rates of glucuronide formation (Vmax) for SCH 39166 were much lower than those of SCH 23390, yet the KM values were similar. Therefore, the average efficiency (Vmax/KM) of SCH 39166 glucuronidation was only 14% that of SCH 23390. These results agree with previous studies in hepatic microsomes from squirrel monkeys. Marked inhibition of SCH 39166 glucuronidation by SCH 23390 and its pharmacologically inactive stereoisomer, SCH 23388, was observed. The inactive stereoisomer of SCH 39166, SCH 39165, was a weak inhibitor. In contrast, substrates for morphine UDP-glucuronosyltransferase (UGT), and p-nitrophenol, an alternative substrate for numerous human hepatic UGTs, did not inhibit SCH 39166 glucuronidation. Further separation of human hepatic UGTs activities using chromatofocusing chromatography indicated that SCH 39166 UGT activity was distinct from human hepatic UGT2B15 and human hepatic pI 6.2 UGT activity. Thus, a unique human hepatic UGT may be involved in SCH 39166 glucuronidation.(ABSTRACT TRUNCATED AT 250 WORDS)