Role of CYP2C9, CYP2C19 and EPHX Polymorphism in the Pharmacokinetic of Phenytoin: A Study on Uruguayan Caucasian Subjects

Abstract

Phenytoin (PHT) oxidative route leads to its main metabolite p-hydroxyphenytoin (p-HPPH), by means of CYP2C9 and CYP2C19. Formation of p-HPPH proceeds via a reactive arene-oxide intermediate. This intermediate can also be converted into PHT dihydrodiol by microsomal epoxide hydrolase (EPHX). The three enzymes are polymorphically expressed and the genetic variants are responsible for changes in the enzyme activity. In order to evaluate the effect that these polymorphisms have on PHT metabolism, PHT and p-HPPH plasma concentrations were measured and the genotype for the three enzymes was assessed in 50 Uruguayan epileptic patients. 30% of the patients were intermediate and 2% were poor metabolizers for CYP2C9, while 20% were intermediate metabolizers for CYP2C19. 44%, 10%, and 46% of subjects had intermediate, increased and decreased activities of EPHX respectively. CYP2C9 was confirmed to be the main responsible enzyme for PHT biotransformation. CYP2C19 seemed to be preponderant in p-HPPH oxidative metabolism. Apart from being responsible for the production of the dihydrodiol metabolite, EPHX also seemed to contribute to pHPPH formation when its activity is low. PHT might be recovered with a decreased activity of EPHX regardless the activity of CYP2C9.

Active Pharmacovigilance in Epileptic Patients: A Deep Insight into Phenytoin Behaviour

“…Moreover, during chronic administration, a lesser exposure of reactive metabolite can be experienced due to the enzyme induction PHT provokes. Our results also evidenced a predominant role of CYP2C9 in PHT biotransformation, while CYP2C19 seems to have a predominant role in p-HPPH biotransformation [31]. A bioequivalence parallel design study in saliva was also carried out with these data.…”

“…To determine CYP2C9 and 2C19 genotype, a conventional PCR was performed for each SNP (rs 1799853 and rs 1057910 for CYP2C9; rs 4244285 and rs 4986893 for CYP2C19). The complete technique is specified in the study performed by our group [31].…”

Lamotrigine-Valproic Acid Interaction Leading to Stevens–Johnson Syndrome

“…Previous work has suggested that the predisposition to such skin reactions evidenced with the use of AEDs is based on a genetic abnormality in the detoxification of reactive metabolites of the drugs [ 28 ]. Our research group has been working on this topic with phenytoin; in this case, EPHX is involved in arene oxide detoxification, so we started to investigate EPHX polymorphisms in patients with AED therapy [ 29 , 30 ]. However, in the case of LTG, both Maggs et al [ 12 ] and Chen et al [ 13 ] research groups conclude that an arene oxide is formed and mainly an enzymatic conjugation with GSH takes place as the glutathione adduct was recovered in the bile.…”

The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug‐resistant epilepsy

“…53,54 PHT is mainly metabolized by CYP2C9, so low or high activity of this enzyme is associated with decreased or increased PHT clearance, respectively, thus higher or lower plasma levels. 55,56 Similarly, genetic influences on phenobarbital metabolism are related mostly to CYP2C19 polymorphism. Therefore, patients with low activity of this enzyme showed a reduction in phenobarbital clearance.…”