N-OXIDE FORMATION: A NEW ROUTE FOR INACTIVATION OF THE ANTIHISTAMINIC CHLORCYCLIZINE

¹ The Wellcome Research Laboratories, Burroughs Wellcome & Co. (U.S.A.), Inc., Tuckahoe, New York

Chlorcyclizine is metabolized to an N-oxide which lacks antihistaminic activity when measured in vitro. After administration of 50 mg/kg p.o. of chlorcyclizine to female rats, 4.2% of the dose was excreted in urine as the N-oxide metabolite. Evidence was also obtained for the excretion of the N-oxide in urine of human subjects after administration of 150-mg daily doses of chlorcyclizine. Although N-oxides have been postulated to be intermediates in demethylation reactions, chlorcyclizine N-oxide does not appear to be converted directly to norchlorcyclizine. No formation of norchlorcyclizine was detected when chlorcyclizine N-oxide was incubated with a rat liver microsomal enzyme system which extensively demethylates chlorcyclizine. Although administration of the N-oxide results in the formation of norchlorcyclizine, this can occur as follows: chlorcyclizine N-oxide chlorcyclizine norchlorcyclizine.