Effects of age and polytherapy, risk factors of valproic acid (VPA) hepatotoxicity, on the excretion of thiol conjugates of (E)-2,4-diene VPA in people with epilepsy taking VPA.
OBJECTIVE
Valproic acid (VPA) is an antiepileptic drug (AED) used for generalized and absence seizures. It has a rare but potentially fatal hepatotoxicity side effect, and many researchers believe that reactive metabolites of VPA could be involved. We demonstrated here that the thiol conjugates of (E)-2,4-diene VPA were significantly elevated in a high-risk group of patients.


METHODS
Thirty-four patients with seizures were divided into three groups. Group A (n = 14) were being treated with VPA; group B (n = 12) received VPA as well as other AEDs that do not induce P450-VPA metabolism; and group C (n = 8) received VPA and AEDs that induce P450-VPA metabolism. The NAC conjugates of (E)-2,4-diene VPA (NAC I and NAC II) were identified in the urine of patients by gas chromatography/mass spectrography NICI analysis.


RESULTS
VPA monotherapy (group A) or VPA polytherapy with non-P450-enzyme-inducing drugs (group B), showed that patients younger than 7.5 years excreted significantly higher concentrations of the two conjugates compared with older patients (older than 7.5 years) in the same groups (p < 0.05). Patients receiving VPA polytherapy with P450-enzyme-inducing drugs were all older than 7. 5 years (group C). They excreted significantly higher concentrations of NAC I and NAC II compared with patients in groups A and B who were older than 7.5 years (p < 0.05).


CONCLUSIONS
There were no significant differences in the excretion of NAC I and NAC II between patients in group C and those who were 7.5 years or younger in groups A and B. High doses of VPA also were a significant factor associated with elevated NAC I and NAC II among young patients and in polytherapy patients.
Gopaul
Sashi
S
Faculties of Pharmaceutical Sciences and Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Farrell
Kevin
K
Abbott
Frank
F
D000111:Acetylcysteine / Q000378:metabolism / Q000652:urine*; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000927:Anticonvulsants / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000502:physiology; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine*; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism* / Q000652:urine; D008297:Male; D012307:Risk Factors; D014635:Valproic Acid / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use
D000927:Anticonvulsants; D014635:Valproic Acid; D000111:Acetylcysteine