TY - JOUR T1 - THE PHARMACOLOGICAL PROPERTIES OF CHLORPROMAZINE SULFOXIDE, A MAJOR METABOLITE OF CHLORPROMAZINE. A COMPARISON WITH CHLORPROMAZINE JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 328 LP - 337 VL - 118 IS - 3 AU - Neil C. Moran AU - William M. Butler, Jr. Y1 - 1956/11/01 UR - http://jpet.aspetjournals.org/content/118/3/328.abstract N2 - Chlorpromazine sulfoxide, a major metabolite of chlorpromazine, has been found to have vasomotor and central nervous system actions similar to those of chlorpromazine. In dogs chlorpormazine sulfoxide produces orthostatic hypotension and partial inhibition of the pressor responses of l-epinephrine, but is much less acive than chlorpromazine. It does not reverse the vasopressor effect of epinephrine up to the lethal dose. In contrast chlorpromazine produces epinephrine reversal at low doses. The vasopressor actions of l-norepinephrine and tetramethylammonium bromide are only partially blocked by either chlorpromazine or the sulfoxide. In anesthetized, vagotomized dogs the sulfoxide produces orthostatic hypotension and partial blockade of the carotid sinus pressor reflex at doses which cause no evident adrenergic or ganglionic blockade. It is concluded that this represents a central depression of barostatic reflex pathways. Both compounds cause sedation in dogs at low doses, chlorpromazine being about eight times as active as the sulfoxide. With increasing doses both compounds produce tremors and finally clonic and tonic convulsions. The convulsant (loses of the two compounds are nearly equal. Similar central nervous system effects are observed in mice, rabbits and cats. However, the sedative action of the sulfoxide in mice and rabbits is very slight in contrast to the effect in dogs and cats, whereas chlorpromazine produces marked sedation in all of these species. At comparable degrees of sedation in dogs the sulfoxide produces less marked orthostatic hypotension than chlorpromazine and has no epinephrine blocking action in contrast to the marked epinephrine vasomotor reversal produced by chlorpromazine. In dogs, both compounds potentiate the anesthetic action of hexobarbital, chlorpromazine being about ten times more active than the sulfoxide. In mice, however, the sulfoxide produces only negligible potentiation compared with the marked activity of chlorpromazine in this species. The intraperitoneal LD50 of the sulfoxide in mice was 163 ± 1.42 mgm./kgm. compared to 190 ± 7.7 mgm./kgm. for chlorpromazine. The difference between these two values is significant at the 1 per cent level. It is concluded that the sulfoxide metabolite of chlorpromazine differs from chlorpromazine in terms of pharmacological action not only quantitatively but also qualitatively in two respects. One, it has only negligible epinephrine-blocking action in dogs, and two, in mice and rabbits it is nearly devoid of central nervous system depressant effects. ER -