Effects of Ethanol on Metabolism of Benzodiazepine Hypnotics.

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We investigated the pharmacokinetic effects of nitrazepam (NZP, 5 mg), a benzodiazepinehypnotic, and rilmazafone hydrochloride (RMZ, 2 mg), a benzodiazepine prodrug with andwithout ethanol (0.7 g/kg body weight).<BR>The study was carried out using the double-blind cross-over blockade design with placeboand vehicle. There were no significant differences in the pharmacokinetic parameters betweenhypnotics alone and hypnotics with ethanol, except for mean residence time (MRT) of RMZ . However, individual variations were found in the serum concentrations of the two hypnotic safter the ethanol consumption as indicated by pharmacokinetic parameters, C<SUB>max</SUB> and absorption rate. Furthermore, the AUC was lowered in NZP and increased in RMZ in 3 out of8 volunteers with ethanolcombined treatments . These findings were interpreted to reflect thedifferences in metabolic processes between NZP and RMZ; RMZ is metabolized throughdemethylation, while nitro-reduction is involved in the metabolism of NZP.<BR>Regarding RMZ, the serum concentrations of the active metabolites, M-1, M-2, M-Aand M-3 were also measured in two volunteers. Ethanolcombined treatments caused a higherconcentration of M-1 in comparison with RMZ treatment alone. This might be due toblockade of the demethylation process from M-1 to M-2 by ethanol.
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