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Diazepam

26 de January de 2021

Monopgraph

Therapeutic action

Diazepam is a long acting benzodiazepine indicated for the treatment of anxiety and insomnia, for opioid and alcohol withdrawal as a muscle relaxant. It is also used as an anticonvulsant to treat status epilepticus or febrile seizure.

Related genes and polymorphisms to study

Genes recommended for determination prior to starting therapy:

GeneCYP2C19. Alleles  *2 , *3 and *17

There are others alleles (* 4, * 5, * 6) as well, all non-functional, although they are very rare and its role is not completely confirmed. In total, about 31 polymorphisms have been described. But most are very rare and in practice it is considered sufficient to determine the * 2, * 3 and * 17 ones for clinical practice.

More information

The FDA warns of the risk associated with a decreased CYP2C19 activity on diazepam product information, and highlighted in the following information:

There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and 2C19). Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation”.

Metabolism

Metabolismo del Diazepam. Coyright PharmGKB. With permission to Eugenomic given by PharmGKB and Standford University. T.E. Klein et al. “Integrating Genotype and Phenotype. Information: An overview of the PharmGKB project”. The Pharmacogenomis Journal (2001) 1: 167-70
Metabolismo del Diazepam. Coyright PharmGKB. With permission to Eugenomic given by PharmGKB and Standford University. T.E. Klein et al. “Integrating Genotype and Phenotype. Information: An overview of the PharmGKB project”. The Pharmacogenomis Journal (2001) 1: 167-70

Diazepam is metabolized in the liver by enzymes of the P-450 cytochrome system. The main enzymes in metabolism are CYP3A4 and CYP2C19, although many other minor active CYP are involved in the processing of diazepam. The major route of elimination transforms diazepam in nordiazepam, an active metabolite generated by CYP2C19 and CYP3A4. Subsequently nordiazepam is transformed to oxazepam by the action of CYP3A4. A secondary route transforms diazepam in temazepam by main active enzyme CYP3A4 and is mostly eliminated by glucuronidation and becomes oxazepam by CYP2C19. Both pathways converge at oxazepam formation which is eliminated after conjugated with glucuronic acid.

Other information to consider

Besides CYP2C19, diazepam is also metabolized by CYP3A4. The studies do not support that the use of CYP3A4 inhibitors affect diazepam response in normal situations, but the effects of diazepam can be enhanced further in patients with compromised CYP2C19 activity, used PMs or CYP2C19 inhibitors such as omeprazole or lansoprazole. Be careful with drugs that affect the pharmacokinetics of diazepam, particularly cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole according to FDA.

Conclusions

PM Individuals for CYP2C19 have higher levels of diazepam in blood due to poor elimination of the drug. This may result in increased adverse effects such as sedation. It has been observed that PM individuals have four times longer diazepam activity and if used in anesthesiology it also prolongs the emergency sedation. In PM patients it is convenient to use lower doses of diazepam or, if appropriate, an alternative drug which elimination is not dependent on CYP2C19 genotype. Temazepam is benzodiazepine drug acting shorter than diazepam, but with similar indication and without sensitivity to CYP2C19 activity.

Marc Cendrós BertranLicenciado en BiologíaMáster en Asesoramiento Genético

Last modified: Sep 6, 2017 @ 09:59 am

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