Increases in metabolism of valproate and excretion of 6β-hydroxycortisol in patients with traumatic brain injury: Valproate and 6β-hydroxycortisol in brain injury

Aims The objectives of this study were to determine the effect of brain trauma on the multiple pathways of metabolism of valproate and to evaluate the use of the urinary 6 beta-hydroxycortisol to cortisol ratio in predicting changes in hepatic metabolism induced by brain injury. Methods Fourteen patients with severe head injuries received a 15 mg kg(-1) loading dose and a maintenance dose of valproate to maintain therapeutic plasma concentrations. A minimum of one steady state trough blood sample and one dosage interval urine were collected during days 3-6 and during days 7-14 post-injury. Total and unbound valproate plasma concentrations were determined by gas chromatography-flame ionization detection (GC-FID) with and without ultrafiltration. Urinary valproate metabolites were measured by gas chromatography/mass spectrometry (GC-MS) (n=10). Urinary 6 beta-hydroxycortisol and cortisol concentrations were determined by high performance liquid chromatography (h.p.l.c.) (n=14). Total intrinsic clearance (CLint) for valproate and individual formation clearances (CLf) to its major metabolites were calculated. Data obtained during baseline (days 3-6) were averaged for each patient and were compared with averaged data obtained from days 7 to 14 using a paired t-test. Results Statistically significant increases in the CLint, CLf of VPA glucuronide, 2-ene-VPA, and 4-OH-VPA pathways and the 6 beta-hydroxycortisol to cortisol ratio were found. The percent change in the 6 beta-hydroxycortisol to cortisol ratio correlated significantly with the changes in the CLint of valproate. Conclusions Brain trauma results in induction of multiple pathways of valproate metabolism and increases in the 6 beta-hydroxycortisol to cortisol ratio, suggesting a non-specific enzyme induction in response to head injury.