N,N′-Diallylpentobarbital (DAPB) metabolites and their effects on pentobarbital-induced sleep and hepatic drug-metabolizing enzymes

Abstract

1. The biological half-life (t_1/2) of N,Ns′-diallylpentobarbital (DAPB) in brain after i.p. injection to mouse was 96 min (first phase) and 11 h (second phase). The t_1/2 values in plasma were 102min and 9.4h, respectively, after i.p. injection. After intracerebroven-tricular (i.c.v.) administration, the t_1/2 values in brain and plasma were 18 and 120 min, and 42 and 177 min, respectively.

2. Following i.p. administration of 2-¹⁴C-DAPB (80mg/kg), 58% of the ¹⁴C was excreted in the urine in 72 h. Several urinary metabolites were identified by g.l.c.-mass spectrometry, DAPB was metabolized by three major pathways, i.e., ω-1 hydroxylation, epoxide-diol pathway and N-deallylation.

3. The effects of DAPB and its metabolites on pentobarbital (PB)-induced sleep were examined after i.p., i.v. and i.c.v. administration. Metabolite 1 [M-1; (ω-1)-hydroxy-DAPB], an active metabolite, exhibited the most potent prolonging effect.

4. M-1 and other metabolites, as well as unchanged DAPB, showed significant inhibitory effects on mouse hepatic drug-metabolizing enzymes.