Characterization of plasma acylcarnitines in patients under valproate monotherapy using ESI-MS/MS

Abstract

Objectives: The effect of administration of the antiepileptic drug valproate (VPA), on the composition of the plasma acylcarnitine profile (including free carnitine) was investigated. Design and methods: Plasma samples were obtained from 18 individuals (13♂:5♀; 15–65y) on long-term treatment with VPA (resulting in plasma levels of 14.6–135.0 mg/L; therapeutic conc.: 40–100 mg/L). Acylcarnitines (AC) in plasma were quantified by electrospray tandem mass spectrometry (ESI-MS/MS). Results: VPA was found to increase the levels (mean ± SD, μM) of 3-hydroxy-isovalerylcarnitine (0.10 ± 0.04; controls: 0.02–0.06), C14:2 acylcarnitine (0.11 ± 0.05; controls: 0.02–0.08), propylglutarylcarnitine (0.06 ± 0.05; controls: 0.00–0.04), and C18-0H-acylcarnitine (0.09 ± 0.05; controls: 0.00−0.04). The free carnitine (C) (42.2 ± 9.0; controls: 22.3–54.9) and the total carnitine (52.3 ± 10.1; controls: 26.5–73.6) were not significantly altered by VPA. Other AC (C2-C18, monounsaturated and hydroxylated) were all within the control range and especially no increase of C8 (valproyl) carnitine was observed. A positive correlation was found between the ratios [AC] / [C] ( p < 0.05) or [long-chain AC (C10-C18)] / [C] ( p < 0.09) with the plasma VPA concentration. Conclusions: The unequivocal increase in 3-hydroxy-isovalerylcarnitine is consistent with the increase of 3-hydroxy-isovaleric acid observed in urine of VPA treated patients. This finding suggests an interaction mechanism of VPA with specific enzymes, namely involved in leucine metabolism. Adult patients under VPA monotherapy do not suffer from carnitine deficiency; the effect of the accumulating acylcarnitines is ill-defined.