Establishing individual metabolite patterns for patients on valproate therapy

Abstract

The aim of this study was to establish individual metabolic profiles of patients receiving valproate (VPA) mono- or polytherapy in order to estimate inter- and intraindividual variability under normal conditions. Serum levels of VPA and 15 metabolites were measured by gas chromotography/mass spectrometry (GC/MS) with selected ion monitoring (SIM). Because of a huge inter-subject variability, calculating means for large epileptic populations resulted in broad and vague ranges for serum levels of VPA and its metabolites. It therefore remained difficult to recognize any significant alteration in the individual metabolic profile. Over long term periods, within-patient changes appeared to be much less intense than inherent interindividual differences. In epileptics consecutively receiving various forms of polytherapy, alterations in the metabolic profiles occurred. Therefore, integrating different kinds of co-medication into a single polytherapy group seemed to be inadequate. An adult patient on VPA monotherapy, suffering form intrahepatic metastasis and renal insufficiency, showed an extremely altered metabolic pattern, with the 4-ene and the omega-/omega1-metabolites being strongly elevated and the major beta-metabolites (E)-2-ene and (E,E)-2,3'-diene being significantly diminished. We suggest determining the individual metabolic profile, consisting of accessible major and minor metabolites, for every patient when VPA therapy has been started or been modified. The moment any clinical complications arise, the previously obtained specific pattern of the individual can be taken as reference in order to assess the possible presance of significant alterations which might indicate or even cause any severe side effects. There seems to be no need of monitoring metabolite levels of the average patient continuously except for the high risk group (e.g. infants under 3 years age receiving polytherapy) which exhibited the highest between-subject as well as within-patient variability.

Abnormal alterations in the metabolic patterns of patients on valproate therapy

“…We tried to establish the speci® c metabolic pattern for every patient when therapy had been started or substantially modi® ed. Thus, the base reference pattern represented the normal condition of the individual (Kreher et al 2001). A boy (patient HSM), who had been a triplet premature birth, was admitted to the Department of Pediatrics at the age of 8 months, suOE ering from BNS-like seizures (Blick-Nick Salaam : saltatory spasm, infantile massive spasm, jacknife seizures) and cerebral motor disturbance (Table 1).…”

“….8 " t 0.95,99¯1 .99 ; 5-OH, t 5-OH¯2 .6 " t 0.95,99 ; 4-keto ; PGA), as well as the 4-ene (formed by d-dehydrogenation) and the 2,4-diene, were enhanced, whereas mitochondrial b-oxidation (2,3« -diene ; 3-OH ; 3-keto) and the 3-enes were less aOE ected (Kreher et al 2001). Compared with the common state, the metabolic system was altered in the initial serum sample obtained from the infantile patient HFRM (HFRM 2).…”

Analysis of variability of concentrations of valproic acid (VPA) and its selected metabolites in the blood serum of patients treated with VPA and patients hospitalized because of VPA poisoning

“…The mean concentration of 4-ene-VPA in toxicological patients was six times higher than in patients treated with VPA (0.84 ±0.59 mg/l vs. 0.14 ±0.06 mg/l), similarly to the mean concentration of VPA which exceeded 5.8 times the mean therapeutic concentration of VPA in the study group (306.74 ±158.17 mg/l vs. 53.28 ±12.96 mg/l; Table IV). Comparable results for the mean concentration of 4-ene-VPA in patients treated with VPA in monotherapy were obtained by Kreher et al (0.15 ±0.12 mg/l) [21]. Significantly different mean concentrations of 4-ene-VPA, amounting Dyskusja W przebiegu biotransformacji kwasu walproinowego na największą uwagę zasługuje szlak β-oksydacji, który w terapii kwasem walproinowym stanowi najistotniejszą przemianę I fazy biotransformacji VPA [17].…”

“…IV). Porównywalne wyniki średniego stężenia 4-en-VPA u pacjentów leczonych VPA w monoterapii uzyskali Kreher et al (0,15 ±0,12 mg/l) [21]. W grupie otrzymującej wysokie dawki terapeutyczne VPA (74,9 ±12,9 mg/kg m.c./ Archiwum Medycyny Sądowej i Kryminologii Archives of Forensic Medicine and Criminology dobę) w porównaniu z dawkami standardowymi VPA (17,8 ±6,4 mg/kg m.c./dobę) stwierdzono istotnie różne średnie stężenia 4-en-VPA wynoszące odpowiednio 0,44 ±0,13 mg/l i 0,08 ±0,06 mg/l [22].…”

A psychotic episode associated with the Atkins Diet in a patient with bipolar disorder

“…Valproate, or 2‐propylpentanoic acid, is a branched‐chain fatty acid that is metabolized both by glucuronization and oxidation. There is significant variation in the pattern of valproate metabolism within and between individuals (6). The oxidative pathway occurs within the mitochondria and is subject to auto‐induction (7) and is capable of complete metabolism of valproate via beta oxidation to carbon dioxide and ketone bodies (8).…”