PP139—Association of ABCB1, ABCC2, CYP2C9 and CYP2C19 polymorphism with phenytoin plasma concentrations

Abstract

Epilepsy is the most prevalent chronic neurologic disorder that affects 65 million people worldwide. Phenytoin (PHT) is 1 of the most widely prescribed antiepileptic drugs (AEDs); however, large interindividual variability in doses and concentrations has been observed in epilepsy treatment with PHT. Functional polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, and drug targets have been suggested to contribute to this genetic variability. To evaluate the association of CYP2C9, CYP2C19, ABCB1, and ABCC2 polymorphism on PHT plasma levels in epileptic patients. The present investigation was carried out in 57 consecutive patients (16–65 years) suffering epilepsy and treated with phenytoin. Approval from the institutional biomedical research ethics committee and the informed consent of patients was obtained before enrollment into the study. Genomic DNA was isolated from blood samples by standard technique. Genotyping of CYP2C9*2, CYP2C19*2 and *3, ABCB1 C1234T, C3435T, G2677A/T, ABCC2 G24A, and G1249A was performed by real-time PCR using allele-specific probes, and CYP2C9*3 by PCR-RFLP. PHT plasma levels were determined by radioimmunoassay. Twenty-six patients showed PHT therapeutic levels (10–20 µg/mL), 24 subtherapeutic and 7 supratherapeutic. Three cases, 2 CYP2C9 *1/*2, and 1 CYP2C19*1/3, had subtherapeutic levels. Patients with wild-type ABCB1 and ABCC2 genotypes exhibited a tendency to have increased PHT plasma levels than patients with mutant genotypes. PHT plasma levels showed great variability among patients that was not statistically significant correlated to the genetic polymorphisms analyzed, although ABCB1 and ABCC2 wild-type genotypes showed a trend toward higher levels. Further investigations are needed with other candidate genes and a larger sample.