Mechanism of N,N'-diallylpentobarbital potentiation of pentobarbital-induced sleep in mice.

Potentiation mechanism of pentobarbital (PB)-induced sleep by N,N'-diallylpentobarbital (DAPB) was studied in mice. DAPB significantly prolonged the PB [40 mg/kg, intraperitoneal (i.p.)]-induced sleeping time by two routes of administration [intravenous (i.v.) and intracerebroventricular (i.c.v.)], nevertheless DAPB alone was devoid of hypnotic activity even by both routes of administration (i.v. and i.c.v.). In addition, DAPB (160 and 320 mg/kg, i.p.) significantly prolonged the sleeping time induced by i.c.v. injection of PB (200 micrograms/mouse). The brain PB half-life (T1/2) of DAPB (80 mg/kg, i.p.) treated group (9.0 h) was 13-fold longer than that of the control (0.7 h). The plasma PB half-life (T1/2) of DAPB treated group (15.2 h) was longer than that of the control (0.6 h). Moreover, DAPB significantly decreased the activities of ethylmorphine (EM) N-demethylase and aniline hydroxylase, and the content of cytochrome P-450 in mouse liver microsomes. The inhibitory effect of DAPB (40 mg/kg, i.p.) on the mouse hepatic drug-metabolizing enzymes was shown til 6 h after administration. DAPB exhibited non-competitive inhibition on the EM N-demethylase activity in vitro. These results indicate that DAPB prolongs the PB-induced sleeping time by both its depressant action to the central nervous system (CNS) and inhibitory effect on the hepatic drug-metabolizing enzymes.