Increases in metabolism of valproate and excretion of 6beta-hydroxycortisol in patients with traumatic 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 6beta-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 6beta-hydroxycortisol and cortisol concentrations were determined by high performance liquid chromatography (h.p.l.c.) (n = 14). Total intrinsic clearance (CL[int]) for valproate and individual formation clearances (CL[f]) 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 CL(int), CL(f) of VPA glucuronide, 2-ene-VPA, and 4-OH-VPA pathways and the 6beta-hydroxycortisol to cortisol ratio were found. The percent change in the 6beta-hydroxycortisol to cortisol ratio correlated significantly with the changes in the CL(int) of valproate.
CONCLUSIONS: Brain trauma results in induction of multiple pathways of valproate metabolism and increases in the 6beta-hydroxycortisol to cortisol ratio, suggesting a non-specific enzyme induction in response to head injury.