Pharmacokinetics of diazepam in epileptic patients and normal volunteers following intravenous administration.

Abstract

1 The pharmacokinetics of diazepam following intravenous administration have been investigated in six normal volunteers and nine epileptic patients receiving chronic antiepileptic drug therapy. 2 After intravenous administration, serum diazepam levels declined biexponentially in all subjects. The elimination half‐life was significantly shorter and the plasma clearance significantly higher in the patients than in the normal volunteers. 3 Serum N‐desmethyldiazepam levels were higher and the time to peak serum concentration was earlier in the epileptic patients than in the controls. 4 It is suggested that the metabolism of diazepam is induced in patients treated with enzyme inducing antiepileptic drugs, although a protein binding interaction between valproic acid and diazepam may contribute to the higher plasma clearance in the epileptic patients taking sodium valproate.

Study of potential drug-drug interactions between benzodiazepines and four commonly used antiepileptic drugs in mice

“…17 Metabolism of diazepam has been reported to be enhanced as a result of induction of hepatic drug-metabolizing enzymes following phenytoin therapy as shown in an earlier study of Kutt and Harden (1999) 18 and Dhillon and Richens (1981). 10 However, in the present study, the combination of sub-effective doses of phenytoin and diazepam showed synergistic (additive) effect (combination showed 100% protection). This could be because, diazepam is metabolized by CYP2C19 isoform of cytochrome P450.…”

“…Phenytoin and phenobarbitone also metabolized by same isoform so concurrent administration of BZD, may increase plasma concentration of phenytoin or phenobarbitone by decreasing its rate of metabolism. 10 Similarly, BZD are also metabolized by CYP3A4 and CBZ is also metabolized by CYP3A4. Hence, similar drug interaction may be occurring between these drugs.…”

“…9 Concomitant administration of AEDs (phenytoin, phenobarbitone, sodium valproate, CBZ) and diazepam or clonazepam have produced variety of drug interactions in clinical as well in vivo and in vitro animal studies. [10][11][12][13] As a few such studies have been reported, the present experimental study was undertaken with four conventional AEDs, phenytoin, CBZ, sodium valproate, and phenobarbitone, combined with two BZD diazepam or clonazepam, to find out whether diazepam or clonazepam modify the effect of these AEDs when they are co-administered. i.e., whether any significant drug interaction is possible between diazepam, clonazepam, and AEDs in a single dose.…”

Pharmacokinetic Interactions Between Antiepileptic Drugs

“…Since all benzodiazepines are mainly eliminated by hepatic metabolism and are highly bound to plasma proteins, interactions are expected both with metabolic inducers and inhibitors and with protein binding displacers. Indeed, inducer anti epileptic drugs have been shown to increase the clearance of c1oba-zam, [235][236][237] diazepam, [238,239] c1onazepam [240][241][242][243][244] and c1orazepate-derived N-desmethyldiazepamP45] lowering their plasma concentrations. For c1obazam, this interaction leads to an accumulation of the pharmacologically active N-demethyl metabolite.…”

Single dose pharmacokinetic study of clobazam in normal volunteers and epileptic patients.

“…Ohnhaus et al (1979) showed that the metabolism of diazepam in man was increased following the induction of liver microsomal enzymes by antipyrine. Dhillon & Richens (1981) found that the elimination half-life of an i.v. dose of diazepam is significantly shorter and the plasma clearance significantly higher in enzyme-induced epileptic patients than in normal volunteers.…”