PharmGKB: The Pharmacogenomics Knowledge Base

Phenytoin Pathway     under review

  Liver Pharmacokinetics: Genes involved in the metabolism of phenytoin in the human liver cell.  
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Phenytoin PK Pathway
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DESCRIPTION:  Phenytoin is one of the most widely-prescribed drugs used to treat epilepsy. The anti-convulsant is associated with a drug hypersensitivity reaction resulting in the need for drug monitoring. Skin rashes often appear at the onset of adverse drug reactions.

The pharmacokinetics of phenytoin is fairly well studied. Up to 90% of phenytoin is metabolized to hydroxyphenytoin by CYP2C9. In particular, the CYP2C9*3 variant has been shown to be associated with the maximum dose of phenytoin (the *3 form shows significant reductions in metabolism). However, CYP2C9*2 was not found to have such an association (PMID:15805193). CYP2C19 also converts phenytoin to hydroxyphenytoin, to a lesser extent in the liver. CYP1A2 has been shown to catalyze the reaction in liver microsomes (PMID: 11038165).

Hydroxyphenytoin can be converted to a catechol by several P450 enzymes. The catechol spontaneously oxidizes to quinone and semiquinone forms. CYP2C19 was found to be the most effective catalyst of catechol formation, however CYP2C9 and CYP3A4 may be responsible for the majority of the transformation due to their predominance in the liver as compared to CYP2C19. CYP3A5, CYP3A7 and CYP1A2 were also shown to catalyze the catechol conversion to a smaller degree (PMID: 10901705 and 11038165). CYP2C9*3 variants displayed diminished activity as compared to the *1 and *2 variants. (PMID:10901705)

It has been shown that the majority of the phenytion is excreted as hydroxyphenytoin O-glucuronide. Hydroxyphenytoin is glucuronidated by UGTs, specifically UGT1A1, UGT1A4, UGT1A6 and UGT1A9. It has been proposed that this glucuronidaton prevents a peroxidase-mediated conversion of hydroxyphenytoin to a toxic reactive metabolite which can oxidize proteins, lipids and DNA. (PMID: 15855726)

As skin rashes occur, extrahepatic metabolism of phenytoin have also been studied. CYP2C18, reported to be expressed in the skin, has been shown to catalyze the primary and secondary hydroxylation steps. (PMID: 16359177)
AUTHORS:M.W. Carrillo
DATE POSTED:April 28, 2006
DATE LAST UPDATED:October 4, 2009
phenytoin cyp2c9 cyp2c19 cyp1a2 cyp2c9 cyp3a4 cyp3a7 cyp1a2 cyp2c19 cyp3a5 ugt1a6 ugt1a9 ugt1a1 ugt1a4
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