Valproic acid and diazepam interaction in vivo.

Abstract

I The effect of oral administration of sodium valproate (1500 mg daily) on the distribution and elimination kinetics of intravenously administered diazepam in six healthy volunteers has been studied. 2 During valproate administration the unbound fraction of diazepam in serum increased approximately two fold. This was accompanied by a significant increase in apparent volume of distribution and plasma clearance of diazepam. 3 There was a positive correlation between the change in free fraction and the increase in both apparent volume of distribution and plasma clearance of the drug. 4 The concentration of unbound diazepam in serum (calculated from the percent free diazepam and total serum concentration) was significantly higher during valproate administration. Both the intrinsic clearance and volume of distribution of unbound drug were significantly reduced. 5 Mean serum N-desmethyldiazepam levels were significantly lower during valproate coadministration. 6 These results suggest that valproic acid displaces diazepam from plasma protein binding sites and inhibits its metabolism.

Differential effects of valproic acid and enzyme‐inducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients.

“…Since the gastrointestinal absorption of nimodipine is considered to be almost complete (Meyer et al, 1983;Raemsch et al, 1985), this finding cannot be ascribed to improved absorption and is most likely explained by inhibition of first-pass metabolism. This explanation would be consistent with previous reports indicating that valproic acid may inhibit the oxidative metabolism of phenytoin (Perucca et al, 1980), diazepam (Dhillon & Richens, 1982) and phenobarbitone (Kapetanovic etal., 1981), as well as the glucuronide conjugation of lamotrigine (Jawad et al, 1987). The fact that nimodipine half-life was not prolonged in valproate-treated patients does not argue against the occurrence of metabolic inhibition because, as discussed above, the elimination rate of this compound is more dependent on hepatic blood flow than on enzyme activity.…”

In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)

“…The metabolism of diazepam is mediated mainly by CYP2C19 and CYP3A4, but CYP2C9 may also be involved [36]. Therefore, inhibition of CYP2C9 by valproic acid may explain the reported modest reduction in the clearance of unbound diazepam [8]. The metabolism of phenobarbitone involves glucosidation, glucuronidation [37] and CYP2C19-mediated oxidation [38], but the contributions of other CYP isoforms are not known.…”

“…It can affect the pharmacokinetics of several drugs including phenytoin [1±3], phenobarbitone [4±7], diazepam [8], nimodipine [9], amitriptyline [10] and clomipramine [11], consistent with inhibition of their metabolism. These drugs are mainly metabolized by different cytochrome P450 (CYP) isoforms.…”

Interactions Between Anticonvulsant and Psychoactive Drugs

“…VPA displaces diazepam from plasma protein binding sites in vitro (69) and in vivo (71), with a concomitant inhibitory effect of VPA on diazepam metabolism, so that diazepam effects are expected to be enhanced in VPA-treated patients.…”