SINGLE DOSES OF VALPROATE (VAL) REDUCE KETONEMIA IN INFANT NFANT MICE: REVERSAL BY L-CARNITINE

Abstract

We have reported that chronic VAL administration reduced plasma β-hydroxybutyrate (β-OHB) levels in suckling mice and fasting epileptic children. This is a study of the effect of single doses of VAL in mice, and possible therapeutic measures. Plasma β-OHB levels (mean ± SE) in 2 to 10-d-old mice (number in parentheses) 30 min after s.c. VAL injection are given below.In other mice, 15 mg/kg of VAL reduced liver free carnitine (CARN) levels 47% in 30 min (74.5 ± 9.2 μmol/kg (4) vs 140 ± 14 in controls (4), P<0.001). Since CARN is essential for long-chain fatty acid oxidation (hence ketogenesis), we examined the effect of concomitant administration of 2.5 mmol/kg L-CARN with 10 mg/kg of VAL (0.06 mmol/kg). The addition of L-CARN increased plasma β-OHB levels from 0.416 ± 0.013 mM (4) (VAL alone) to 0.606 ± 0.028 mM (4) (P<0.001) (still 37% less than in controls, 1.06 ± 0.03 mM (4), P<0.001). Injection of 2.5 mmol/kg of L-CARN with a smaller dose of VAL, 5 mg/kg, increased plasma β-OHB levels from 0.586 ± 0.039 mM (4) (VAL alone) to 0.843 ± 0.037 mM (4) (P=0.003) (not different from the control value, 0.979 ± 0.059 mM (4)). Decreased liver CARN levels suggest one explanation for VAL-induced hypoketonemia in mice and possible stratagems for prophylaxis and/or treatment of VAL-associated hepatotoxicity in infants and children.