Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8993099 | Drug Metabolism and Pharmacokinetics | 2005 | 9 Pages |
Abstract
The anticonvulsant agent phenytoin (5,5-diphenylhydantoin) is mainly excreted as 5-(4â²-hydroxyphenyl)-5-phenylhydantoin (4â²-HPPH) O-glucuronide in humans. Previously, we demonstrated that the glucuronidation of 4â²-HPPH is catalyzed by multiple UDP-glucuronosyltransferases (UGTs) of UGT1A1, UGT1A4, UGT1A6, and UGT1A9. Since 4â²-HPPH may be bioactivated to a reactive metabolite by peroxidase, the glucuronidation in considered to be a detoxification pathway. In the present study, we investigated the relationship between the extent of interindividual variability in the urinary excretion levels of 4â²-HPPH and its O-glucuronide and genotyping of CYP2C9, CYP2C19, UGT1A1, UGT1A6, and UGT1A9. 4â²-HPPH and its glucuronide in urine samples from 15 patients to whom phenytoin was administered were measured by liquid chromatography-tandem mass spectrometry. When the molar ratio of 4â²-HPPH O-glucuronide/4â²-HPPH was calculated as an index of glucuronidation, a large interindividual variability (11 fold) was observed in the 15 patients. Phenytoin is metabolized to 4â²-HPPH by CYP2C9 and CYP2C19 in which there are genetic polymorphisms. Although 5 patients were genotyped as heterozygotes of mutated alleles of CYP2C9 or CYP2C19 genes, no relationship with the interindividual difference in the total excretion levels of 4â²-HPPH and its O-glucuronide was observed. The UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A6*2 alleles were found in 1, 3, 6, and 8 patients, respectively. Although there was no relationship between the genetic polymorphisms of UGT1As and the interindividual difference in the 4â²-HPPH glucuronidation, the large interindividual variability of 4â²-HPPH glucuronidation may contribute to interindividual differences in toxic reactions to phenytoin.
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Authors
Hiroyuki Yamanaka, Miki Nakajima, Yusuke Hara, Miki Katoh, Osamu Tachibana, Junkoh Yamashita, Tsuyoshi Yokoi,