Potential relationships between transaminase abnormality and valproic acid clearance or serum carnitine concentrations in Japanese epileptic patients.
This study tested the hypothesis that the determinants of mild liver injury are prerequisites for more severe idiosyncratic hepatotoxicity. This study verified whether the possible risk factors for rare idiosyncratic valproic acid (VPA)-induced hepatotoxicity, VPA clearance and/or serum carnitine concentrations are common to those for a mild elevation in transaminases in VPA-treated patients. VPA clearance was calculated in 172 Japanese patients with epilepsy, using a non-linear mixed-effects regression program. Carnitine concentrations were determined in a subset of 60 patients. The relationships between VPA clearance, carnitine concentration and levels of transaminases and ammonia were evaluated by Pearson's correlation coefficients. The final model of VPA apparent clearance (CL/F) was as follows: CL/F (L h(-1) = 0.012 x (BW/40)(0.34) x dose(0.55) x 0.90(gender) x 1.32(PHT) x 1.11(CBZ) x 1.12(PB), where BW = total body weight (kg); gender = 1 if female, 0 if male; PHT/CBZ/PB = 1 if phenytoin, carbamazepine, or phenobarbital, respectively, is coadministrated, otherwise 0. Either a higher VPA clearance or acyl/free carnitine ratio and a lower total and/or free carnitine concentration, but not VPA concentration, were associated with the mild elevation in transaminases or ammonia. These results support the initial hypothesis, while also helping to clarify the mechanism of severe idiosyncratic hepatotoxicity with VPA.
Goto
Shuji
S
Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Seo
Takayuki
T
Hagiwara
Takashi
T
Ueda
Kentaro
K
Yamauchi
Tsuyuko
T
Nagata
Shiro
S
Ando
Yukio
Y
Ishitsu
Takateru
T
Nakagawa
Kazuko
K
D000293:Adolescent; D000328:Adult; D000641:Ammonia / Q000378:metabolism; D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics; D001835:Body Weight; D002331:Carnitine / Q000097:blood*; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007223:Infant; D007564:Japan; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D012307:Risk Factors; D012737:Sex Factors; D000637:Transaminases / Q000187:drug effects* / Q000378:metabolism; D014635:Valproic Acid / Q000009:adverse effects* / Q000493:pharmacokinetics
D000927:Anticonvulsants; D014635:Valproic Acid; D000641:Ammonia; D000637:Transaminases; D002331:Carnitine