Hyperpyrexic interaction between debrisoquine and pethidine in rabbits

Pethidine injection into rabbits treated with debrisoquine either acutely or chronically resulted in severe interaction and fatal hyperpyrexia. Pretreatment of rabbits with p-chlorophenylalanine, chlorpromazine, or crypoheptadine protected them against the interaction, while alpha-methyl-p-tyrosine was ineffective. In addition the administration of debrisoquine into 5-HTP pretreated rabbits produced a severe interaction and hyperpyrexia. The hepatic N-demethylation of pethidine was significantly inhibited by debrisoquine pretreatment both in vivo and in vitro. The debrisoquine-pethidine interaction could be due to 5-HT potentiation or prevention of uptake. Alternatively it could be due to inhibition of biotransformation of pethidine by debrisoquine. However, neither mechanism by itself alone could be held responsible as the sole explanation of the interaction.