Effects of sodium valproate on haem biosynthesis in man: implications for seizure management in the porphyric patient.
The short-term effects of sodium valproate (VPA) on haem biosynthesis were assessed in a placebo-controlled crossover trial in eight healthy male subjects who ingested VPA 500 mg t.i.d. and matched placebo for 5 days. All showed augmented activity of leucocyte 5-aminolaevulinate synthase (ALA-S) activity, the rate-limiting enzyme of the haem biosynthetic pathway, following 3 and 5 days of VPA treatment (P less than 0.001). This was accompanied by increased urinary excretion of 5-aminolaevulinic acid (ALA; P less than 0.02) and total porphyrins (P less than 0.01). Mean (+/- SD) total VPA concentrations on day 3 (89 +/- 16 mg 1-1) and day 5 (91 +/- 22 mg 1-1) were within the target range for the drug. The long-term effects of VPA administration were examined in epileptic patients on established monotherapy. Leucocyte ALA-S activity (P less than 0.001), and daily urinary excretion of porphobilinogen (P less than 0.01) and total porphyrins (P less than 0.01) were all higher than in age-matched controls. No significant differences in erythrocyte ALA-dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase activities were found between the groups. These data suggest that VPA is porphyrinogenic in man and cannot be recommended as safe for seizure management in the porphyric patient.
D000624:5-Aminolevulinate Synthetase / Q000097:blood; D000293:Adolescent; D000328:Adult; D004334:Drug Administration Schedule; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D006418:Heme / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011162:Porphobilinogen / Q000378:metabolism / Q000652:urine; D011164:Porphyrias / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D011166:Porphyrins / Q000096:biosynthesis / Q000652:urine; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D011166:Porphyrins; D006418:Heme; D014635:Valproic Acid; D011162:Porphobilinogen; D000624:5-Aminolevulinate Synthetase