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Physiologic disposition of H3-cyclazocine in nontolerant, tolerant and abstinent dogs.

S. Mulé,C. Gorodetzky

Published 1966 in Journal of Pharmacology and Experimental Therapeutics

ABSTRACT

This study was initiated in order to correlate the distribution and metabolism of H3-cyclazocine with its pharmacologic effects. A method specific for the estimation of H3-cyclazocine in biologic tissue and fluids was developed with a minimal sensitivity of 3 ng/ml of biologic material. Urine, fecal and plasma levels were determined in the same nontolerant, tolerant and abstinent dogs following a 1.25-mg/kg (free base) subcutaneous injection of H3-cyclazocine. The mean percentage recovery of the administered dose from urine and feces for both free and conjugated drug over a period of 120 hr was 43.7% from nontolerant dogs, 58.5% from tolerant dogs and 40.7% from abstinent dogs. Mean plasma levels of free cyclazocine reached a maximum of 156 ng/ml at 30 min in both nontolerant and tolerant dogs, and then fell rapidly to a level of 6 ng/ml at 8 hr in these dogs. Maximal levels of 304 and 361 ng/ml of conjugated cyclazocine were found at 90 min in the nontolerant and tolerant dogs, respectively. Mean values of 60 to 80 ng/ml of conjugated cyclazocine were obtained for these animals at 8 hr. Maximal mean levels of 1215 and 1259 ng/g were obtained at 1 hr in cerebral cortex gray matter of nontolerant and tolerant dogs, respectively. In white matter, the mean levels were 895 to 1108 ng/g. At 6 hr, the values had fallen to 36 to 56 ng/g in nontolerant dogs, and 100 to 117 ng/g in tolerant dogs. The levels of drug in subcortical areas were similar to those observed in the cerebrum. No drug was found in the central nervous system of a 24-hr abstinent dog. The levels of drug in certain peripheral tissues paralleled central nervous system values, but were quite high in lung, kidney, spleen, liver and adrenals. The bile contained extremely high levels of free and conjugated drug. The results indicated that potency of cyclazocine but not latency of abstinence was correlated with distribution, and that the drug was markedly metabolized.

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