Mechanism of prolongation of pentobarbital-induced sleeping time by empenthrin in mice

The effect of empenthrin, a synthetic pyrethroid, on pentobarbital (PTB)-induced sleeping time was examined in mice and rats. In mice, pretreatment with empenthrin prolonged PTB-induced sleeping time in a dose-dependent manner. The maximum effect on PTB-sleeping time was noted when mice were pretreated orally with empenthrin 2-4 h before PTB injection. However, empenthrin did not change the sleeping time induced by diethyl ether which is hardly metabolized in liver. Empenthrin inhibited the clearance of serum PTB in mice, but did not change the PTB concentration in serum at which animals recovered from sleeping. To examine the effect of PTB on metabolic enzymes in mouse liver, PTB was incubated aerobically with a hepatic microsomal fraction in the presence of NADPH at 37 degrees C. Empenthrin inhibited the in vitro metabolism of PTB dose-dependently. In rats, empenthrin neither changed the PTB sleeping time, nor inhibited the clearance of serum PTB. No inhibitory effect of empenthrin was observed on the in vitro metabolism of PTB using rat hepatic microsomal fraction. These findings indicate that empenthrin prolongs PTB-sleeping time in mice through an inhibition of the PTB-metabolizing enzyme(s) in the liver, an effect that does not occur in rats. Also, there is a clear species-specificity in the inhibitory effect of empenthrin on the PTB-metabolizing enzyme(s).