Article date: May 2000
By: Daniel B. McLaughlin, Jaymie A. Andrews, Wayne D. Hooper, Graeme R. Cannell, Mervyn J. Eadie, Ronald G. Dickinson, in Volume 49, Issue 5, pages 409-415
Aims The study aimed to show whether autoinduction of valproate (VPA) along its β‐oxidation pathway occurred upon chronic dosing in humans.
Methods Twelve young volunteers without active illness took sodium valproate (NaVPA) 200 mg orally 12 hourly for 3 weeks. On days 7 and 21, serial blood samples and all urine passed over an interdosing interval from 08.00 to 20.00 h were collected for analysis of VPA and certain metabolites.
Results Plasma AUC(0,12 h) of VPA was significantly lower on day 21 than on day 7 (2.40 vs 2.84 µmol ml−1 h, 95% CI for the difference 0.13–0.81 µmol ml−1 h). Significant differences in plasma AUC(0,12 h) of the β‐oxidation metabolites E‐2‐en‐VPA and 3‐oxo‐VPA were not found. However, formation clearances of plasma VPA to urinary E‐2‐en‐VPA and 3‐oxo‐VPA were significantly increased from day 7 to day 21 (0.010 vs 0.024 and 2.57 vs 3.60 ml kg−1 h−1, respectively, 95% CI for the differences −0.025 to −0.004 and −1.72 to −0.34 ml kg−1 h−1, respectively). Formation clearances to VPA‐glucuronide (0.534 vs 0.505 ml kg−1 h−1) and 4‐OH‐VPA (0.112 vs 0.110 ml kg−1 h−1) were not significantly different.
Conclusions Regular low dose VPA intake in humans over a period of 3 weeks appears to be associated with a small induction of its metabolism by the β‐oxidation pathway, but not by glucuronidation or 4‐hydroxylation.
DOI: 10.1046/j.1365-2125.2000.00191.x
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