The majority of patients with epilepsy maintain seizure control during pregnancy. The apparently higher risk of seizures among women treated with oxcarbazepine and the more frequent increases in drug load in the oxcarbazepine and lamotrigine cohorts prompts further studies on relationships with pharmacokinetic changes. Risks associated with status epilepticus appear to be lower than previously reported.

Aims The study aimed to show whether autoinduction of valproate (VPA) along its b-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 signi®cantly lower on day 21 than on day 7 (2.40 vs 2.84 mmol ml x1 h, 95% CI for the difference 0.13±0.81 mmol ml x1 h).Signi®cant differences in plasma AUC(0,12 h) of the b-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 signi®cantly increased from day 7 to day 21 (0.010 vs 0.024 and 2.57 vs 3.60 ml kg x1 h x1 , respectively, 95% CI for the differences x0.025 to x0.004 and x1.72 to x0.34 ml kg x1 h x1 , respectively). Formation clearances to VPA-glucuronide (0.534 vs 0.505 ml kg x1 h x1 ) and 4-OH-VPA (0.112 vs 0.110 ml kg x1 h x1 ) were not signi®cantly 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 b-oxidation pathway, but not by glucuronidation or 4-hydroxylation.

We assessed the effects of felbamate (FBM) on the disposition of valpr oic acid (VPA) in healthy volunteer men. Eighteen subjects received sodium VPA, 400 mg/day for 21 days. Plasma and urine samples were taken on day 7 to document the steady-state disposition of VPA alone. From day 8 to day 21, subjects received placebo or FBM at the following doses (mg/day): 1,200, 2,400, 3,000, or 3,600 (n = 2-4 per group). Many adverse events (AE) occurred from about day 10; 2 subjects dropped out and 1 continued on a reduced FBM dose. Pharmacokinetic studies were repeated on day 21 for the 16 subjects who completed the study. FBM was measured in plasma and urine by high-performance liquid chromatography (HPLC). VPA and its 2-en, 4-en, and 3-oxo metabolites in plasma, and VPA (nonconjugated and total), and its 3-oxo and 4-hydroxy metabolites in urine were measured by gas chromatography/mass spectrometry (GC/MS). Mean plasma FBM trough concentrations on day 21 ranged from 26.9 mu g/ml (1,200 mg dose) to 76.8 mu g/ml (3,600-mg dose). Mean plasma VPA C max values were 32-42 mu g/ml in the various subgroups when VPA only was administered. Higher plasma VPA levels were observed when FBM was administered concurrently (55.4-63.8 mu g/ml). The excretion of 3-oxo-VPA in urine was significantly lower on day 21 than on day 7, whereas VPA-glucuronide was significantly increased. The effects of FBM on VPA disposition were dose dependent and were maximal at approximately 2400 mg/day. FBM has caused significant inhibition of the beta-oxidation pathway for VPA metabolic clearance, and this had been largely compensated by increased VPA glucuronidation.