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

• Published in: Clinical toxicology (Philadelphia, Pa.) Vol. 57; no. 8; pp. 743 - 747
• Main Authors: Boels, David, Chhun, Stéphanie, Meyer, Géraldine, Lelièvre, Bénédicte, Souday, Vincent
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 03.08.2019
• Subjects: Clobazam; Clobazam - blood; Clobazam - poisoning; CYP2C19; Cytochrome P-450 CYP2C19 - genetics; Drug Overdose - diagnosis; Drug Overdose - drug therapy; Drug Overdose - etiology; Drug Overdose - genetics; GABA-A Receptor Agonists - blood; GABA-A Receptor Agonists - poisoning; Homozygote; Humans; Inactivation, Metabolic - genetics; Life Sciences; Male; metabolic; Middle Aged; Mutation; Pharmaceutical sciences; poisoning; polymorphism; Treatment Outcome; polymorphism; poisoning; Clobazam; metabolic
• ISSN: 1556-3650; 1556-9519
• DOI: 10.1080/15563650.2018.1550198

Introduction: Voluntary drug intoxication with benzodiazepines is common and in most cases without consequences. We report an interesting case of voluntary drug intoxication with clobazam (CLB) in a patient with a homozygous mutated CYP2C19 genotype. Case report: A 63-year-old Caucasian man was admitted to an intensive care unit for voluntary drug intoxication with CLB (1200 mg) complicated by prolonged hospitalization (46 days). The levels of CLB and N-desmethylclobazam (NCLB) in plasma were initially 8.3 and 14.8 mg/L. The persistence of a high concentration of NCLB (14.3 mg/L on day 30) suggested a lack of elimination. A homozygous mutated allele of CYP2C19*2 without enzyme activity was discovered. To overcome this phenotype, NCLB metabolism was induced by administering 100 mg of phenobarbital for 10 days, allowing patient improvement. Discussion: 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. The half-life elimination of CLB is 18 h that of NCLB is between 40 and 50 h. However, there is considerable inter-individual variation in the metabolism of CLB and of the report NCLB/CLB under the dependence of genotype of CYP2C19. These polymorphisms are not generally well-known by physicians and may lead to severe poisoning.