Abstract

The metabolism of H³-cyclazocine was studied in nontolerant, tolerant and abstinent dogs after a 1.25-mg/kg (free base) s. c. injection of the drug. Norcyclazocine and cyclazocine were identified in the urine of these dogs after extraction and direct application of hydrolyzed and unhydrolyzed urine samples to chromatographic paper buffered with 0.1 M phosphate or impregnated with silicic acid. The chromatograms were developed with tert.-amyl alcohol-n-butyl ether-water (80:7:13, v/v) or ethyl acetate-methanol-NH₄OH (85:10:5, v/v). A method was developed for the estimation of H³-norcyclazocine in biologic material with a minimal sensitivity of 5 ng/ml. In the urine of nontolerant, tolerant and abstinent dogs, 2.3 to 2.7% of the H³-cyclazocine was recovered as free norcyclazocine and an equal amount as conjugated norcyclazocine. In the feces of these dogs, from 1.5 to 2.4% of the free and 0.02 to 0.7% of the conjugated norcyclazocine was obtained. Norcyclazocine was not found in the brain of the dogs at various time intervals, but the metabolite was obtained in peripheral tissues. Urine samples were subjected to acid and enzymatic hydrolysis, using β-glucuronidase and phenol sulfatase. The data indicated that the conjugate of both cyclazocine and norcyclazocine was a glucuronide. Norcyclazocine (1.0 mg/kg) did not significantly depress the flexor reflex of the chronic spinal dog. It is concluded that norcyclazocine is not an active metabolite of cyclazocine and that 47 to 66% of the administered H³-cyclazocine was accounted for as free and conjugated cyclazocine and norcyclazocine, as determined over a 5-day period.