EFFECTS OF MICROSOMAL MONO-OXYGENASE INHIBITORS UPON THE IN VIVO METABOLISM AND DURATION OF ACTION OF 1-ETHYNYLCYCLOHEXYL CARBAMATE

¹ The Lilly Research Laboratories, Indianapolis, Indiana

The in vivo metabolism, in rats, of ethinamate (1-ethynylcyclohexyl carbamate) was shown to be stimulated by pretreatment with phenobarbital and to be inhibited by 2, 4-dichiloro-6-phenylphenoxyethylamine (DPEA) and 2-chloro-6-phenylphenoxyethylamine (MPEA) as evidenced by parallel changes in plasma and brain ethinamate levels and half-lives and by sleeping times. Ethinamate was not abnormally distributed within the body and it did not bind strongly to plasma protens. The concentration of ethinamate in brain correlated closely with the plasma levels indicating that rapid equilibrium was established between the blood and brain compartments; MPEA was also found to inhibit the metabolism of ethinamate in dogs in vivo. In vitro studies with rat microsomes indicated that MPEA and DPEA exert their in vivo effects by inhibiting the conversion of ethinamate to hydroxyethinamate. These studies suggest that ethinamate may be a valuable model compound for the study of in vivo drug interactions.