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 language | English (US) |
|---|---|
| Pages (from-to) | 54-63 |
| Number of pages | 10 |
| Journal | Epilepsy Research |
| Volume | 71 |
| Issue number | 1 |
| DOIs | |
| State | Published - Sep 1 2006 |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - Paradoxical urinary phenytoin metabolite (S)/(R) ratios in CYP2C19*1/*2 patients
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
PY - 2006/9/1
Y1 - 2006/9/1
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.
KW - Antiepileptic drug
KW - CYP2C19
KW - CYP2C9
KW - Metabolism
KW - Phenytoin
KW - Polymorphisms
KW - p-Hydroxyphenyl phenylhydantoin
UR - http://www.scopus.com/inward/record.url?scp=33747156084&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33747156084&partnerID=8YFLogxK
U2 - 10.1016/j.eplepsyres.2006.05.015
DO - 10.1016/j.eplepsyres.2006.05.015
M3 - Article
C2 - 16815679
AN - SCOPUS:33747156084
VL - 71
SP - 54
EP - 63
JO - Epilepsy Research
JF - Epilepsy Research
SN - 0920-1211
IS - 1
ER -