Related Experiment Video
Updated: Jun 1, 2025

Evaluation of Drug Sorption to PVC- and Non-PVC-based Tubes in Administration Sets Using a Pump
Published on: March 11, 2017
Effect of Valproate Coprescription on Clozapine Pharmacokinetics in Clinical Practice
Robert James Flanagan1, Stephen John Obee1, Alice Hyun Min Kim2
1From the Department of Precision Medicine, Networked Services, Bessemer Wing, King's College Hospital NHS Foundation Trust, London, England.
Background:
Sodium valproate has been coprescribed with clozapine for seizure prophylaxis and for augmentation in treatment-refractory schizophrenia. However, the effect of valproate on clozapine metabolism and on the incidence of clozapine-related side effects is unclear.
Methods:
We compared clozapine dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in smokers and nonsmokers of both sexes in samples submitted for clozapine therapeutic drug monitoring, 1996-2017 in relation to valproate coprescription.
Results:
There were 1217 (665 patients) and 3823 (1600 patients) samples from nonsmokers and from smokers, respectively, who were coprescribed valproate and clozapine. Data from 9774 (5065 patients) and 15,465 (7298 patients) samples from nonsmokers and from smokers, respectively, for whom drugs other than valproate were coprescribed were used as controls. Valproate coprescription in nonsmokers was associated with an increase in average plasma clozapine of 22.5%, suggesting moderate inhibition of clozapine metabolism, but there was no marked effect of valproate coprescription on plasma clozapine in smokers. In all the valproate-treated groups (male and female smokers and nonsmokers), the median plasma norclozapine concentration and the median plasma clozapine-to-norclozapine ratio were significantly lower and higher, respectively, as compared with the controls. Mixed-effects models showed a significant dose-response effect of valproate on lowering the plasma norclozapine concentration and on increasing the plasma clozapine-to-norclozapine ratio.
Implications:
Given the complexity of the effect of valproate coadministration on clozapine pharmacokinetics and the possibility that the toxicity of clozapine may be enhanced in the presence of valproate, the use of these drugs in combination must now be questioned in all patients and not only in women of childbearing age.
More Related Videos
Related Concept Videos
Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance
A study on guinea pigs examined the...
Psychosis: Goals of Pharmacotherapy
Nonlinear Pharmacokinetics: Bioavailability and Protein-Drug Binding
To quantify the extent of bioavailability, pharmacologists often use a parameter called .
Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
Hepatic Drug Clearance: Effect of Protein Binding
For low-extraction-ratio drugs that are less than 80% protein-bound, minor changes in protein binding...
Factors Affecting Drug Response: Overview

