Phenytoin

Monopgraph

Therapeutic action

Phenytoin (also called diphenylhidantoin) is an anticonvulsant drug indicated for the treatment of epilepsy with tonic-clonic (Grand Mal) y psychomotor (temporal lobe) seizures, but not for Petit Mal.

Metabolism

Phenytoin is metabolized in the liver through enzymes pertaining to the CYP450 system, mainly CYP2C9 and CYP2C19 generating an hydroxilated metabolite without activity. Other enzymes also have a role in the transformation of phenytoin, but its importance is much lower. There is a wide interindividual variability in the plasma levels of phenytoin even if the same doses are used, due to variations in the rate of metabolism.

Other factors to be considered

The metabolism of phenytoin takes place through saturable mechanisms, such as due to genetic variants reducing the functionality of the enzyme. Once the saturation point is reached, dose increases as moderate as 10% can be enough to lead to an overdose. The availability of pheytoin to its site of action, in the central nervous system, is affected by the efflux transporter MDR1 (P-glycoprotein). An overexpression of P-glycoprotein is related with therapeutic failure. On the other hand, certain polymorphisms in the ABCB1 gene, encoding P-glycoprotein, have also been related with therapeutic failure for phenytoin.

Conclusions

Phenytoin is a drug with a narrow therapeutic window, and moderate increases in the plasma concentrations can induce significant changes on the response, particularly toxicity. The starting dose is the same for all the genotypes, but the maintenance dose must be adjusted according to the patient’s genotype for CYP2C9 and cYP2C19. In PM patients the maintenance dose should be reduced to 50%, because these patients ae at risk of developing phenytoin toxicity. In IM patients, the dose should be reduced by 25%. Some cases of severe phenytoin toxicity have been reported in CYP2C9 *3/*3 homozygous patients. Valproic acid is not metabolized by CYP2C9 nor CYP2C19 and has been used successfully as an alternative anticonvulsant drug in PM patients experiencing adverse reactions.

The genotype for the ABCB1 gene also determines the efficacy of the treatment. The risk of therapeutic failure is increased with the C allele compared with the T allele. In the CC homozygous patients it is adequate to asses the possibility of using an alternative therapy to control the seizures.

Bibliography

Sayyah, M. et al. (2011). Association analysis of intractable epilepsy with C3435T and G2677T/A ABCB1 gene polymorphisms in Iranian patients. Epileptic Disord 13, 155–65.Sánchez, M. B. et al. (2010). Genetic factors associated with drug-resistance of epilepsy: relevance of stratification by patient age and aetiology of epilepsy. Seizure 19, 93–101.Kesavan R. et al. (2010). Influence of CYP2C9 and CYP2C19 genetic polymorphisms on phenytoin-induced neurological toxicity in Indian epileptic patients. Eur J Clin Pharmacol. 66(7):689-96.Haerian B.S. et al. (2010). ABCB1 C3435T polymorphism and the risk of resistance to antiepileptic drugs in epilepsy: a systematic review and meta-analysis. Seizure.; 19(6):339-46. Epub 2010 Jun 3.Swen J.J. et al. (2008). Pharmacogenetics: from bench to byte. Clin Pharmacol Ther. 2008 May;83(5):781-7.Seo T. et al. (2006). ABCB1 polymorphisms influence the response to antiepileptic drugs in Japanese epilepsy patients. Pharmacogenomics; 7(4):551-61.

MarcBertranCendrósDegree inBiologyMasterinGenetic Counseling

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