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.
Tateoka
Y
Y
Department of Hygienic Chemistry, School of Pharmacy, Hokuriku University, Kanazawa, Japan.
Kimura
T
T
Watanabe
K
K
Yamamoto
I
I
Ho
I K
IK
D000818:Animals; D001921:Brain / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005037:Ethylmorphine-N-Demethylase / Q000032:analysis; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D010424:Pentobarbital / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D012890:Sleep / Q000187:drug effects*
D003577:Cytochrome P-450 Enzyme System; C047654:N,N-diallylpentobarbital; D005037:Ethylmorphine-N-Demethylase; D010424:Pentobarbital