Effect of CPS14217C>A genotype on valproic-acid-induced hyperammonemia.
BACKGROUND
In order to clarify the factors causing hyperammonemia and to predict occurrences during treatment with valproic acid (VPA), we investigated the effect of the genetic polymorphism of carbamoyl-phosphate synthase 1 (CPS14217C>A) on susceptibility of hyperammonemia, together with the effect of coadministration of other anticonvulsants.


METHODS
Seventy-nine patients with epilepsy were enrolled, and five of them had hyperammonemia. Univariate and multivariate logistic regression analyses were performed.


RESULTS
The aspartate aminotransferase level in the patients with hyperammonemia was significantly higher than that in those without hyperammonemia. The risk of hyperammonemia was significantly influenced by the number of anticonvulsants concomitantly administered with VPA. Also, the distribution of the CPS14217C>A genotype differed depending on whether the patients had hyperammonemia or not. No significant effects of CPS14217 genotypes and the number of anticonvulsants coadministered with VPA on the serum concentrations of VPA were observed. The multivariate logistic regression analysis showed that the concomitant administration of two or more anticonvulsants with VPA and the heterozygous or homozygous carrier state of the A allele of the CPS14217C>A polymorphism were independent risk factors for developing hyperammonemia.


CONCLUSIONS
These findings suggested that in epileptic patients undergoing VPA therapy, CPS14217A polymorphism and the number of coadministered anticonvulsants would be considered as risk factors for hyperammonemia, even if the serum VPA concentrations were controlled.
Yagi
Mariko
M
Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine, Kobe, Japan.
Nakamura
Tsutomu
T
Okizuka
Yo
Y
Oyazato
Yoshinobu
Y
Kawasaki
Yoko
Y
Tsuneishi
Shuichi
S
Sakaeda
Toshiyuki
T
Matsuo
Masafumi
M
Okumura
Katsuhiko
K
Okamura
Noboru
N
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000704:Analysis of Variance; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000187:drug effects; D005838:Genotype; D006801:Humans; D022124:Hyperammonemia / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D015994:Incidence; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D012016:Reference Values; D012307:Risk Factors; D017678:Sex Distribution; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects*; D055815:Young Adult
D000927:Anticonvulsants; D005819:Genetic Markers; D014635:Valproic Acid; D002222:Carbamoyl-Phosphate Synthase (Ammonia)