Paradoxical urinary phenytoin metabolite (S)/(R) ratios in CYP2C19*1/*2 patients

Upendra A. Argikar, James C Cloyd, Angela K Birnbaum, Ilo E Leppik, Jeannine M Conway, Smita Kshirsagar, William S Oetting, Erin C. Klein, Rory P Remmel

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Phenytoin (PHT) is primarily metabolized to 5-(4′-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), accounting for 67-88% of an administered dose in humans. p-HPPH is formed by the cytochrome (CYP) 450 enzymes CYP2C9 and CYP2C19, then glucuronidated and excreted into the urine. CYP2C9 catalyses the prochiral formation of (R) and (S)-p-HPPH, and is approximately 40 times more stereoselective towards the formation of the (S) isomer whereas CYP2C19 is not stereoselective. Because of differential stereoselectivity, polymorphisms in the genes can alter the (S)/(R)-p-HPPH ratios. Genotyping for CYP2C9 and CYP2C19 was accomplished by a Taqman based assay. Twelve and twenty-four hour urine samples were collected from 45 epilepsy patients taking PHT under steady-state conditions and (S)/(R) ratios of p-HPPH were determined by chiral HPLC separation. The mean urinary (S)/(R) ratio in the 12-24 h urine collection in subjects homozygous for CYP2C9*1/*1, CYP2C19*1/*1 was 24.2 ± 3.1(n = 21), whereas ratios in CYP2C9*1/*2 and CYP2C9*1/*3 subjects, were 11.1 ± 3.3(n = 7) and 2.7 ± 0.6(n = 2), respectively. One CYP2C9*2/*3 patient had a ratio of 2.1. Unexpectedly, CYP2C9*1/*1, CYP2C19*1/*2 subjects had a mean (S)/(R) ratio as low as 12.9 ± 1.7(n = 12). Our results are generally consistent with single dose PHT studies. However, the (S)/(R)-p-HPPH ratios for the CYP2C9*1/*1, CYP2C19*1/*2 subjects, expected to be in the range of 30-40, were only 12.9, suggesting some undetected linkage disequilibrium between CYP2C9 and CYP2C19 genes that could affect PHT elimination. Furthermore, our study suggests that measurement of urine ratios cannot be used as a marker for genotype determination.

Original languageEnglish (US)
Pages (from-to)54-63
Number of pages10
JournalEpilepsy Research
Volume71
Issue number1
DOIs
StatePublished - Sep 1 2006

Fingerprint

Phenytoin
Urine
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP2C19
Urine Specimen Collection
Linkage Disequilibrium
Cytochromes
Genes
2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a
Epilepsy
Genotype
High Pressure Liquid Chromatography

Keywords

  • Antiepileptic drug
  • CYP2C19
  • CYP2C9
  • Metabolism
  • Phenytoin
  • Polymorphisms
  • p-Hydroxyphenyl phenylhydantoin

Cite this

Paradoxical urinary phenytoin metabolite (S)/(R) ratios in CYP2C19*1/*2 patients. / Argikar, Upendra A.; Cloyd, James C; Birnbaum, Angela K; Leppik, Ilo E; Conway, Jeannine M; Kshirsagar, Smita; Oetting, William S; Klein, Erin C.; Remmel, Rory P.

In: Epilepsy Research, Vol. 71, No. 1, 01.09.2006, p. 54-63.

Research output: Contribution to journalArticle

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abstract = "Phenytoin (PHT) is primarily metabolized to 5-(4′-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), accounting for 67-88{\%} of an administered dose in humans. p-HPPH is formed by the cytochrome (CYP) 450 enzymes CYP2C9 and CYP2C19, then glucuronidated and excreted into the urine. CYP2C9 catalyses the prochiral formation of (R) and (S)-p-HPPH, and is approximately 40 times more stereoselective towards the formation of the (S) isomer whereas CYP2C19 is not stereoselective. Because of differential stereoselectivity, polymorphisms in the genes can alter the (S)/(R)-p-HPPH ratios. Genotyping for CYP2C9 and CYP2C19 was accomplished by a Taqman based assay. Twelve and twenty-four hour urine samples were collected from 45 epilepsy patients taking PHT under steady-state conditions and (S)/(R) ratios of p-HPPH were determined by chiral HPLC separation. The mean urinary (S)/(R) ratio in the 12-24 h urine collection in subjects homozygous for CYP2C9*1/*1, CYP2C19*1/*1 was 24.2 ± 3.1(n = 21), whereas ratios in CYP2C9*1/*2 and CYP2C9*1/*3 subjects, were 11.1 ± 3.3(n = 7) and 2.7 ± 0.6(n = 2), respectively. One CYP2C9*2/*3 patient had a ratio of 2.1. Unexpectedly, CYP2C9*1/*1, CYP2C19*1/*2 subjects had a mean (S)/(R) ratio as low as 12.9 ± 1.7(n = 12). Our results are generally consistent with single dose PHT studies. However, the (S)/(R)-p-HPPH ratios for the CYP2C9*1/*1, CYP2C19*1/*2 subjects, expected to be in the range of 30-40, were only 12.9, suggesting some undetected linkage disequilibrium between CYP2C9 and CYP2C19 genes that could affect PHT elimination. Furthermore, our study suggests that measurement of urine ratios cannot be used as a marker for genotype determination.",
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AU - Argikar, Upendra A.

AU - Cloyd, James C

AU - Birnbaum, Angela K

AU - Leppik, Ilo E

AU - Conway, Jeannine M

AU - Kshirsagar, Smita

AU - Oetting, William S

AU - Klein, Erin C.

AU - Remmel, Rory P

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N2 - Phenytoin (PHT) is primarily metabolized to 5-(4′-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), accounting for 67-88% of an administered dose in humans. p-HPPH is formed by the cytochrome (CYP) 450 enzymes CYP2C9 and CYP2C19, then glucuronidated and excreted into the urine. CYP2C9 catalyses the prochiral formation of (R) and (S)-p-HPPH, and is approximately 40 times more stereoselective towards the formation of the (S) isomer whereas CYP2C19 is not stereoselective. Because of differential stereoselectivity, polymorphisms in the genes can alter the (S)/(R)-p-HPPH ratios. Genotyping for CYP2C9 and CYP2C19 was accomplished by a Taqman based assay. Twelve and twenty-four hour urine samples were collected from 45 epilepsy patients taking PHT under steady-state conditions and (S)/(R) ratios of p-HPPH were determined by chiral HPLC separation. The mean urinary (S)/(R) ratio in the 12-24 h urine collection in subjects homozygous for CYP2C9*1/*1, CYP2C19*1/*1 was 24.2 ± 3.1(n = 21), whereas ratios in CYP2C9*1/*2 and CYP2C9*1/*3 subjects, were 11.1 ± 3.3(n = 7) and 2.7 ± 0.6(n = 2), respectively. One CYP2C9*2/*3 patient had a ratio of 2.1. Unexpectedly, CYP2C9*1/*1, CYP2C19*1/*2 subjects had a mean (S)/(R) ratio as low as 12.9 ± 1.7(n = 12). Our results are generally consistent with single dose PHT studies. However, the (S)/(R)-p-HPPH ratios for the CYP2C9*1/*1, CYP2C19*1/*2 subjects, expected to be in the range of 30-40, were only 12.9, suggesting some undetected linkage disequilibrium between CYP2C9 and CYP2C19 genes that could affect PHT elimination. Furthermore, our study suggests that measurement of urine ratios cannot be used as a marker for genotype determination.

AB - Phenytoin (PHT) is primarily metabolized to 5-(4′-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), accounting for 67-88% of an administered dose in humans. p-HPPH is formed by the cytochrome (CYP) 450 enzymes CYP2C9 and CYP2C19, then glucuronidated and excreted into the urine. CYP2C9 catalyses the prochiral formation of (R) and (S)-p-HPPH, and is approximately 40 times more stereoselective towards the formation of the (S) isomer whereas CYP2C19 is not stereoselective. Because of differential stereoselectivity, polymorphisms in the genes can alter the (S)/(R)-p-HPPH ratios. Genotyping for CYP2C9 and CYP2C19 was accomplished by a Taqman based assay. Twelve and twenty-four hour urine samples were collected from 45 epilepsy patients taking PHT under steady-state conditions and (S)/(R) ratios of p-HPPH were determined by chiral HPLC separation. The mean urinary (S)/(R) ratio in the 12-24 h urine collection in subjects homozygous for CYP2C9*1/*1, CYP2C19*1/*1 was 24.2 ± 3.1(n = 21), whereas ratios in CYP2C9*1/*2 and CYP2C9*1/*3 subjects, were 11.1 ± 3.3(n = 7) and 2.7 ± 0.6(n = 2), respectively. One CYP2C9*2/*3 patient had a ratio of 2.1. Unexpectedly, CYP2C9*1/*1, CYP2C19*1/*2 subjects had a mean (S)/(R) ratio as low as 12.9 ± 1.7(n = 12). Our results are generally consistent with single dose PHT studies. However, the (S)/(R)-p-HPPH ratios for the CYP2C9*1/*1, CYP2C19*1/*2 subjects, expected to be in the range of 30-40, were only 12.9, suggesting some undetected linkage disequilibrium between CYP2C9 and CYP2C19 genes that could affect PHT elimination. Furthermore, our study suggests that measurement of urine ratios cannot be used as a marker for genotype determination.

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