Glucuronidation of the dopamine D-1 receptor antagonists NNC 0756 and NNC 0772 in liver microsomes.
Glucuronidation of the two enantiomeric dopamine D-1 antagonists, NNC 0756 ([(+)-8-chloro-7-hydroxy-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl- 2,3,4,5,tetrahydro-1H-3-benzazepine, acetate]) and NNC 0772 [(-)-8-chloro-7-hydroxy-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine, HCl], was studied in rat and human liver microsomes. In rats, the reaction exhibited biphasic kinetics for both enantiomers as shown by Eadie-Hofstee plots. Both the high- and low-affinity reactions showed a high degree of stereoselectivity, primarily because of the large differences in Km values. For the high- and low-affinity reactions, the (-)-enantiomer, NNC 0772, had a 4- and 6-fold higher Km value, respectively. The difference in Vmax values were less significant, with 3.0- and 1.1-fold higher values for the (-)-enantiomer. Treatment of rats with known inducers of UDP-glucuronosyltransferases, phenobarbital, and 3-methyl-cholanthrene, did not change the kinetics of the reaction. Glucuronidation of the (+)-enantiomer, NNC 0756, was competitively inhibited in rat liver microsomes by the closely related structure, SCH 23388 [S-(-)-8-chloro-7-hydroxy-5-phenyl-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine], with an apparent Ki value of 90 microM. Morphine and 4-hydroxybiphenyl, both known substrates of glucuronosyltransferase, did also inhibit the reaction with Ki values of 604 and 55 microM, respectively. In contrast to rats, glucuronidation of NNC 0756 in human liver microsomes followed Michaelis-Menten kinetics, suggesting the involvement of a single form of glucuronosyltransferase or possibly two forms, with similar affinity for NNC 0756.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Drug Metabolism, Novo Nordisk, Maaleev, Denmark.
K T
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Hansen
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Thomsen
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Bundgaard
D000818:Animals; D001552:Benzazepines / Q000378:metabolism*; D001572:Benzofurans / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism*; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*
D001552:Benzazepines; D001572:Benzofurans; D011954:Receptors, Dopamine; D014535:Uridine Diphosphate Glucuronic Acid; C075357:odapipam; D014453:Glucuronosyltransferase