Phenytoin

Eadie, Mervyn J.

doi:10.1002/9781444316667.ch47

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…Although no significant difference was obtained in any of the comparisons, it should be noted that [PHT] in the NM/IM group remained unchanged despite the decrease in CYP2C19 activity, while the IM/NM group had higher [PHT] not only when compared with the NM/NM group (18% higher), but also with the NM/IM group (17% higher). According to these results, it can be said that PHT metabolism may not be affected when only CYP2C19 activity is decreased owing to the fact that CYP2C9, which has been reported to have a predominant role in PHT metabolism [4], is able to compensate the decrease in CYP2C19 activity. On the other hand, when CYP2C9 activity is decreased, CYP2C19 is not able to compensate it and an increased [PHT] is seen, because of a reduced PHT clearance.…”

Section: Discussionmentioning

confidence: 95%

“…The dihydrodiol can be converted into catechol or conjugated with glucuronide. Less than 5% of the administered dose of PHT is excreted unchanged in urine [1,2,3,4]. …”

Section: Introductionmentioning

confidence: 99%

“…However, this m -isomer seems to be an analytical artefact produced during the acid hydrolysis of urine, which is carried out to separate primary metabolites from the glucuronide conjugates, rather than a natural PHT metabolite [2,4,5]. …”

Section: Introductionmentioning

confidence: 99%

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

Guevara

Maldonado

Uría³

et al. 2017

Pharmaceuticals

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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.

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Section: Discussionmentioning

confidence: 95%

“…The dihydrodiol can be converted into catechol or conjugated with glucuronide. Less than 5% of the administered dose of PHT is excreted unchanged in urine [1,2,3,4]. …”

Section: Introductionmentioning

confidence: 99%

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

Guevara

Maldonado

Uría³

et al. 2017

Pharmaceuticals

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Epoxide Hydrolases

Omiecinski¹,

Yang²,

Laurenzana³

2012

Encyclopedia of Drug Metabolism and Interactions

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Epoxides are three‐membered carbon–oxygen compounds that typically arise from the metabolism of endogenous and xenobiotic compounds via chemical and enzymatic oxidation processes. Many different oxygenase enzymes are capable of forming epoxide derivates, from either arene or alkene substrate; however, the cytochrome P450 monooxygenases are principal contributors to their generation. Certain epoxides are highly electrophilic and chemically reactive, and they have been implicated as initiators of various cellular toxicities, including the formation of DNA mutations and ultimately, cancers. Therefore, it is of vital importance for the organism to regulate levels of these reactive species. A single mammalian enzyme, microsomal epoxide hydrolase (EPHX1, mEH), functions as a predominant pathway responsible for detoxification of xenobiotic epoxides, as well as bioactivation pathway for certain xenobiotic epoxides. In contrast, another important epoxide hydrolase, soluble epoxide hydrolase (EPHX2, sEH), has more recently been established as a mediator of epoxide hydrolysis of several endogenously derived epoxyeicosatrienoic acids (EETs), intermediates resulting from arachidonic acid metabolism. In this respect, EPHX2 is now characterized as an important regulator of physiological processes, such as blood pressure and inflammation, and has emerged as a promising therapeutic target for pharmacological intervention. This chapter reviews the biochemistry, biological regulation, genetics, and pharmacological relevance of these important enzyme systems.

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Phenytoin

Cited by 4 publications

References 46 publications

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

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

Epoxide Hydrolases

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