Notes on Kinetics and Metabolism of Benzodiazepines

Garattini, Silvio; Caccia, Silvio; Carli, Mirjana; Mennini, Tiziana

doi:10.1016/b978-0-08-026382-3.50049-9

Cited by 6 publications

(6 citation statements)

References 20 publications

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“…Diazepam is well recognized to undergo demethylation and oxidative metabolism to active metabolites. The principal metabolite is nordiazepam, which is roughly 4‐fold less potent than diazepam as a modulator of GABA A receptors and as an antiseizure agent in rats . However, levels of nordiazepam in our experiments were only a fraction of that of diazepam, even after sufficient time had elapsed to nearly achieve steady‐state.…”

Section: Discussionmentioning

confidence: 59%

Determination of minimal steady‐state plasma level of diazepam causing seizure threshold elevation in rats

Dhir

Rogawski

2018

Epilepsia

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Section: Discussionmentioning

confidence: 59%

Determination of minimal steady‐state plasma level of diazepam causing seizure threshold elevation in rats

Dhir

Rogawski

2018

Epilepsia

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“…The biological T V2 of the drug ranged from about 6 hours in the dog to about 14 hours in the cat and averaged 60 hours in man. Thus, the elimination kinetics of phenazepam in man can be classified in the same range as the long-acting benzodiazepines (15). The largest normalized (value/dose), Cmax was also observed in man, and the rat gave the lowest value.…”

Section: Discussionmentioning

confidence: 86%

Species differences in phenazeram kinetics and metabolism

Zherdev

Caccia

Garattini

et al. 1982

European Journal of Drug Metabolism and Pharmacokinetics

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The kinetic profiles of phenazepam and its hydroxylated derivative were compared in rat, dog, cat and man after administration of single oral doses of the parent compound. The absorption of phenazepam was reasonably rapid in all the species studied. Blood peak concentrations (Cmax) were reached at 1 h in rats (0.32 +/- 0.03 microgram/ml), at 0.5 h in dogs 0.54 +/- 0.10 microgram/ml), at about 2 h in cats (1.65 +/- 0.23 microgram/ml), about only at 4 h in man (0.038 microgram/ml) at the highest dose tested. The largest normalized (value/dose) Cmax and area under the curve (AUC) were observed in man, while the rat gave the lowest values. The half-life of phenazepam was about 60 h in man, 13.72 +/- 2.09 h in the cat, 6.35 +/- 2.32 h in the dog and 7.49 +/- 1.88 h in the rat (beta-half-life). 3-OH-phenazepam was rapidly detected in cat, rat, and dog blood but no measurable amounts (less than 3 ng/ml) were found in human blood. At the oral doses tested, the ratio of the AUC for 3-OH-phenazepam to phenazepam was 0.01, 0.48, and 0.53 in the dog, rat, and cat, respectively. The half-life of the metabolite was shorter than that of the parent compound in the dog, but it was comparable in the rat and longer in the cat. The results suggest that 3-OH-phenazepam might contribute to the overall pharmacological effects of the parent compound in those species in which it accumulates in significant amounts.

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“…Different metabolic pathways exist for different benzodiazepines because of structural differences of the compounds (Garattini et al 1981;Greenblatt & Shader 1974;Schwartz 1973). This results in different metabolites, different lengths of action and different elimination half-lives.…”

Section: 3 Metabolism and Excretionmentioning

confidence: 98%

“…Peak blood levels appear within 30 to 180 minutes (Garattini et al 1981). For emergency situations intravenous diazepam or clonazepam may be used as the recommended route of administration.…”

Section: Absorptionmentioning

confidence: 99%

Disposition of Anticonvulsants in Childhood

Morrow

Richens

1989

Clinical Pharmacokinetics

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There have been great advances in our understanding of the childhood epilepsies within recent years and at the same time there has been increasing awareness of the pharmacokinetic properties of the anticonvulsant drugs. It has been increasingly recognised that pharmacokinetic parameters of anticonvulsants are not constant, but are subject to influences by a number of physiological variables over which age is a major determinant. As changes in pharmacokinetic parameters will alter dosage requirements, dosage regimens cannot be transferred from one age group to another without the risk of underdosing or overdosing. Drug monitoring techniques are being increasingly used as a guide to correct dosing but knowledge of the limitations of monitoring is as important as knowledge of potential benefits for monitoring to be used correctly.An overview of the important pharmacokinetic properties of anticonvulsant drugs is provided, with emphasis on findings in children where such data are available.Modem anticonvulsant therapy probably began around the beginning of this century with the introduction of phenobarbitone (phenobarbital). It quickly replaced potassium bromide, which previously had been the drug of choice despite its severe toxic effects. Phenytoin (then called diphenylhydantoin) was introduced in 1937 by Merritt and Putnam, who also advanced methods for the preclinical assessment of anticonvulsant agents. Since then, and particularly in the last 20 years, a number of additional anticonvulsant drugs have been developed, as has a greater understanding of their pharmacokinetic properties. In parallel, there have been substantial advances in understanding the evolution of the childhood epilepsies. It has become increasingly recognised that there may be important differences in drug pharmacokinetics due to many physiological variables over which age and disease state are major determinants.

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Notes on Kinetics and Metabolism of Benzodiazepines

Cited by 6 publications

References 20 publications

Determination of minimal steady‐state plasma level of diazepam causing seizure threshold elevation in rats

Determination of minimal steady‐state plasma level of diazepam causing seizure threshold elevation in rats

Species differences in phenazeram kinetics and metabolism

Disposition of Anticonvulsants in Childhood

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