Effects of sodium valproate on haem biosynthesis in man: implications for seizure management in the porphyric patient

Abstract

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.

N-Alkylprotoporphyrin Formation and Hepatic Porphyria in Dogs After Administration of a New Antiepileptic Drug Candidate: Mechanism and Species Specificity

“…The unsaturated metabolite of valproic acid is chemically related to AIA (Baillie, 1988). Not surprisingly, valproic acid has been documented to be porphyrogenic in human (McGuire et al, 1988). Compound 1 might undergo the same two parallel reactions, ␤-hydroxylation to compound 3 and desaturation of the butyramide (Fig.…”

Neurological complications of porphyria

“…19 Whereas some AEDs are known to exacerbate porphyric attacks, others are thought to be safe for porphyria, controlling seizures without exacerbating the attacks. [21][22][23][24][25][26][27][28][29][30][31][32][33] Five of our patients were treated with GBP, two of them for neuropathic pain (8, 9, and 11). Pain was reported to be improved to some extent in two of these patients.…”

Acute intermittent porphyria in two patients on anticonvulsant therapy and with normal erythrocyte porphobilinogen deaminase activity.

“…It has been suggested that carbamazepine reduces PBG deaminase activity (Rapeport et al, 1984) but it has subsequently been appreciated that it is the activity of ALA dehydratase that is reduced by this drug (McGuire et al, 1988a (McGuire et al, 1988b) and yet interestingly PBG deaminase activity in both patients rose on discontinuing valproate (Figure 1 (Rapeport et al, 1984;McColl et al, 1980). Sodium valproate, although not an enzyme inducer, stimulates porphyrin production in normal individuals by mechanisms as yet unclear (McGuire et al, 1988b). As PBG deaminase is a secondary ratecontrolling step in haem biosynthesis (Brodie et al, 1977b), marked induction of the primary rate-controlling enzyme ALA synthase could result in accumulation of porphyrin precursors similar to that occurring in AIP.…”