Nonstationary disposition of valproic acid during prolonged intravenous infusion: contributions of unbound clearance and protein binding

Abstract

Circadian variations in disposition have been observed for a variety of agents, including anticonvulsants. Valproic acid (VPA), an anticonvulsant used to control generalized and partial seizures, has exhibited diurnal oscillations in steady-state concentrations during long-term administration to humans and non-human primates. The present study was conducted to assess potential diurnal changes in the disposition of VPA during prolonged i.v. infusion in rats. Animals, maintained on a strict 12-h per day light cycle, were equipped with venous cannulae and an arterial microdialysis probe. VPA was administered as a 50-mg/kg loading dose followed by a 42 mg/kg/h infusion for 70 h. Blood and microdialysate samples were obtained at timed intervals after establishment of steady-state throughout two complete light/dark cycles; and total (serum) and unbound (microdialysate) VPA was determined by gas chromatography. Modest oscillations (6-7 h period) in total and unbound VPA were observed; clearance and binding parameters were not different between light and dark periods. However, unbound clearance increased, and unbound fraction decreased, with time over the course of the infusion. These results suggest that time-dependent changes in VPA disposition occur in rats, although oscillations in steady-state concentrations do not appear to be diurnal in nature.

Fluctuating and constant valproate administration gives equivalent seizure control in rats with genetic and acquired epilepsy

“…1008 mg/kg per day), 42 mg/kg/h was administered to the intermittent group. A previous study by Arens and Pollack 31 showed sustained therapeutic plasma levels by hourly continuous infusion of 42 mg/kg of VPA. The longer time between the administration of VPA doses (e.g.…”

“…and was found to produce therapeutic serum levels of VPA (600-1800 mmol/L). 31 Drug delivery was carried out via an EEG/infusion cable (made in house) connected through an EEG and fluid swivel, allowing free movement, to a 32 channel video-EEG system (Compumedics Limited, Melbourne, Australia) and a multisyringe programmable pump (KDS 230, Walker Scientific, Wangara, Australia) as previously described. 28 To assist in preventing infusion lines clotting, animals were given a daily 0.1 mL bolus of heparinised saline (20 IU/mL).…”

Long-Term Valproate Treatment Increases Brain Neuropeptide Y Expression and Decreases Seizure Expression in a Genetic Rat Model of Absence Epilepsy

“…All rats (n = 17) were given heparinised saline as described above for 3 days and on the 4 th day rats were weighed and assigned randomly to either 42 mg.kg −1 .hr −1 valproate (Sigma, USA) (n = 9) a dose that is known to suppress seizures [38], [40] or saline (n = 8). After 5 days of treatment (day 8) rats were euthanized with an overdose of sodium pentobarbital (1 ml/kg i.p.…”

A novel system allowing long-term simultaneous video-electroencephalography recording, drug infusion and blood sampling in rats

“…Animals in the chronic infusion experiment (n = 38) first received saline (0.9% NaCl) for 4-5 days, at a rate of 1 ml/h followed by two infusion periods (3-5 days each) of 42 mg/kg valproate (Sigma, USA) (Arens and Pollack, 2001) (1 ml/h) separated by two days of saline (0.9% NaCl, 1 ml/h) (Table 1). Infusion solutions contained 4 IU/ml of heparin to prevent blood clotting.…”