Species difference in diazepam metabolism and anticonvulsant effect

General Pharmacology and Neuropharmacology of Benzodiazepine Derivatives

“…Antipentetrazole activities of various benzodiazepines in the rat were reported by BANZIGER (1965), MARCUCCI et al (1968 a), BANERJEE and YEOH (1977), MATTHEWS and MCCAFFERTY (1979), in the rabbit by BANZIGER (1965), and in the guinea pig by MARCUCCI et al (1971 a). In rats, KLEINROK et al (1977) found that the antipentetrazole action of chlordiazepoxide, diazepam, oxazepam, and nitrazepam was enhanced by 5-HTP, 5-methoxytryptamine (combined with pargyline), or fenfluramine.…”

Biliary Excretion of Conjugated Hydroxyl Benzodiazepines after Administration of Several Benzodiazepines to Rats, Guinea Pigs, and Mice

“…The two metabolites N-demethyldiazepam and N-methyloxazepam are metabolized through hydroxylation and N-demethylation, respectively, to form the final common metabolite oxazepam (4). The extent of these processes is different according to the animal species both in uitro ( 5 , 6 ) and in uiuo (7,8).…”

The Effects of Age and Liver Disease on the Disposition and Elimination of Diazepam in Adult Man

“…The metabolite, desmethyldiazepam, has similar (but probably weaker) pharmacological activity to the parent drug (3,44,45), but lack of knowledge of its kinetics of disposition and elimination when administered per se prevented any analysis of the effect of age upon its formation, distribution, and elimination after diazepam administration. However, the lower concentrations, the delay in appearance, and the time to peak concentration of this metabolite with increasing age would be consistent with an age-dependent change in the distribution of both the metabolite and the parent drug.…”

“…After recovery from acute viral hepatitis, the diazepam half-life returned almost to normal values; No statistically significant correlation was noted between the diazepam ti (a) in patients with cirrhosis or hepatitis (and drug clearance in cirrhosis) and any of the standard liver function tests. The reduced clearance of diazepam in patients with acute and chronic parenchymal liver disease suggests that this drug should be used with caution, especially on a prolonged basis, in (1)(2)(3)(4)(5). In man, the major biotransformation pathways include demethylation to Ni-desmethyldiazepam, the major metabolite detectable in the plasma, and, to a lesser extent, hydroxylation to form Ni-methyloxazepam.…”

“…These two metabolites are hydroxylated and N-demethylated, respectively, to form oxazepam. The hydroxylated metabolites are then conjugated to their respective glucuronides, with oxazepam glucuronide as the major urinary product (1)(2)(3)(4)(5). Most studies of the plasma elimination of diazepam have been limited to data obtained after oral administration of the drug, particularly after prolonged therapy.…”