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

  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},
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… 

Influence of CYP2C19 Polymorphism and Concomitant Antiepileptic Drugs on Serum Clobazam and N-Desmethyl Clobazam Concentrations in Patients With Epilepsy

The interaction between NCLB and other antiepileptic drugs showed marked differences among CYP2C19 phenotypes and measurement of the serum N CLB concentration is clinically useful for identifying the PM phenotype.

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


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.

Therapeutic Drug Monitoring of Clobazam and Its Metabolite—Impact of Age and Comedication on Pharmacokinetic Variability

The pharmacokinetic variability of CLB and its metabolite NCLB in clinical practice is extensive, and is influenced by drug–drug interactions, age, and pharmacogenetics, therefore valuable in patient management.

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.



Clinical relevance of genetic polymorphisms in the human CYP2C subfamily.

  • J. Goldstein
  • Biology, Medicine
    British journal of clinical pharmacology
  • 2001
The human CYP2Cs are an important subfamily of P450 enzymes that metabolize approximately 20% of clinically used drugs and each member of this subfamily has been found to be genetically polymorphic.

Cytochrome P450 Isozymes and Antiepileptic Drug Interactions

  • R. Levy
  • Biology, Chemistry
  • 1995
Summary: Recent findings about individual isoforms of the cytochromes P450 involved in the metabolism of phe‐nytoin (PHT) and carbamazepine (CBZ) make prediction of inhibition‐based interactions

Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin.

Recombinant CYP2C19 6 had negligible catalytic activity toward S-mephenytoin compared with CYP 2C19 1B, which is consistent with the conclusion that CYP1C19*6 represents a PM allele.

Effect of felbamate on clobazam and its metabolite kinetics in patients with epilepsy.

The authors report preliminary findings on the effect of the new generation antiepileptic drug (AED) felbamate (FBM) on steady state plasma concentrations of clobazam (CLB), a benzodiazepine

A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin.

A new allele is identified in Caucasian PMs which contains an A-->G mutation in the initiation codon which indicates that CYP2C19*4 represents a new PM allele.

Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese.

A new mutation is identified in Japanese poor metabolizers, consisting of a guanine to adenine mutation at position 636 of exon 4 of CYP2C19, which creates a premature stop codon.

A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin.

Two new allelic variants that contribute to the PM phenotype in Caucasians are isolated and Restriction fragment length polymerase chain reaction tests were developed to identify the new allele variants.

Interactions between clobazam and standard antiepileptic drugs in patients with epilepsy.

We retrospectively collected plasma level assessments performed in 96 adult patients with epilepsy on stable monotherapy, including 9 patients on clobazam (CLB), 34 on carbamazepine (CBZ), 24 on

Kinetics and metabolism of clobazam in animals and man.

Abstract 1 The pharmacokinetic behaviour of the psychotropic drug clobazam, a 1,5 benzodiazepine, and its metabolism were studied with the 14C-labelled compound in rats, dogs, monkeys and man. The