Metabolites of an antipsychotic chiral pyrroloisoquinoline and their effect on prolactin secretion in the rat

SJ Kolis, TH Williams, TF Mowles, B Burghardt, V Toome and MA Schwartz

Racemic-2, 6-dimethyl-3-ethyl- 4,4a,5,6,7,8,8a, 9-octahydro-4a,8a-trans- 1H-pyrrolo[2, 3-g]isoquinoline-4-one hydrochloride (rac-l HCl) appeared to be equipotent to haloperidol in increasing serum prolactin levels in rats although only about one-twentieth as potent as haloperidol in reversing dopamine-inhibited prolactin release by rat anterior pituitary cells in vitro. The metabolism of 14C-labeled rac-l HCl was studied in rats and the activity of metabolites was evaluated in the in vitro prolactin release assay. Four metabolites, two C11-monohydroxy diastereomers and one C10-and one C12-monohydroxy metabolite, plus parent drug were isolated from the urine of rats administered [14C]rac- l HCl. These were shown to be optically active, indicating that the racemic drug was stereoselectively metabolized. All of the identified metabolites plus those in extracts of urine and feces proved inactive in the in vitro prolactin release assay. In addition, the brains of three rats removed 1 hr after single 3.6 mg/kg oral doses of [14C]rac-l HCl contained essentially only unchanged drug. We conclude that the potency of rac-l HCl in raising serum prolactin levels is not due to the formation of active metabolite(s) in vivo.

Volume 227, Issue 3, pp. 652-657, 12/01/1983
Copyright © 1983 by American Society for Pharmacology and Experimental Therapeutics