Evidence of Polymorphic CYP2C19 Involvement in the Human Metabolism of N-Desmethylclobazam

@article{Contin2002EvidenceOP,
  title={Evidence of Polymorphic CYP2C19 Involvement in the Human Metabolism of N-Desmethylclobazam},
  author={Manuela Contin and Simonetta Sangiorgi and Roberto Riva and Antonia Parmeggiani and Fiorenzo Albani and Agostino Baruzzi},
  journal={Therapeutic Drug Monitoring},
  year={2002},
  volume={24},
  pages={737-741}
}
The authors report preliminary findings on the potential contribution of CYP2C19 isoenzyme to the human metabolism of N-desmethylclobazam (N-CLB), the main active metabolite of clobazam (CLB), a benzodiazepine frequently used as add-on therapy in patients with refractory epilepsy. Two children on CLB treatment showing extremely high plasma concentration/dose ratio (C/D) of N-CLB and metabolite/parent drug ratio (N-CLB/CLB), suggestive of a putative poor metabolizer (PM) phenotype, were tested… 

Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy

The efficacy of low-dose CLB therapy was significantly influenced by CYP2C19 polymorphisms and dosage should be started with a low dose and dosage increased until N-CLB serum concentration reaches 1100 ng/mL or until the desired effect is acquired, a recommendation that is particularly important for PMs.

Polymorphism of human cytochrome P450 enzymes and its clinical impact

Current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) is highlighted to understand the large interindividual variability in drug clearance and responses in clinical practice and to improve the efficacy and safety of both prospective and currently available drugs.

[Pharmacogenetics and antiepileptic drug metabolism: implication of genetic variants in cytochromes P450].

The identification of interindividual variability in the response to AEDs may allow the personalized treatment with the aim of maximize the efficiency and minimize risk, regardless of the clinical variability and adverse effects could be manifest in a minority of the patients.

Impact of CYP2C19 polymorphisms on the efficacy of clobazam therapy.

YP2C19 genotype had an impact on the efficacy of clobazam, thus indicating that N-clobzam plays an important role in long-term clobrazam therapy.

In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19.

The specific cytochrome P450 (P450) isoforms mediating the biotransformations of clobazam (CLB) and those of its major metabolites, N-desmethylclobazam (NCLB) and 4'-hydroxyclobazam were identified

IN VITRO AND IN VIVO INHIBITORY EFFECT OF STIRIPENTOL ON CLOBAZAM METABOLISM

The major in vitro inhibitory effect of STP on CLB metabolism and mostly on NCLB biotransformation is consistent with the changes in vivo in CLB and NCLb plasma concentrations in children treated by the association CLB/STP.

Clinical consequences related to a defective elimination of clobazam caused by homozygous mutated CYP2C19 allele

NCLB is the major active metabolite of CLB with a longer half-life and much higher steady-state plasma concentrations compared to the parent drug and there is considerable inter-individual variation in the metabolism ofCLB and of the report NCLB/CLB under the dependence of genotype of CYP2C19.

Pharmacokinetics of Clobazam and N-Desmethylclobazam in Children with Dravet Syndrome Receiving Concomitant Stiripentol and Valproic Acid

This is the first simultaneous pharmacokinetic model for clobazam and N-CLB in epileptic children, described by a one-compartment model with first-order absorption, and elimination, formation and elimination of N- CLB were also first- order processes.

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