Toloxatone pharmacokinetics in the plasma and cerebrospinal fluid of the rabbit

The pharmacokinetics of toloxatone (5 and 10 mg kg-1, i.v.) was studied in anaesthetized rabbits. There was a biexponential decline in plasma concentration with time. No differences were observed in the pharmacokinetic parameters with the increase of the dose. The terminal half-life was short (47.4 +/- 2.8 and 41.5 +/- 4.2 min for 5 and 10 mg kg-1, respectively). The total clearance was 79 +/- 18 mL min-1 after a dose of 5 mg kg-1 and 106 +/- 40 mL min-1 after a dose of 10 mg kg-1. The volume of distribution was 5.8 +/- 2.8 (5 mg kg-1) and 5.4 +/- 1.8 L (10 mg kg-1). The average percentage of toloxatone bound to plasma protein was 30% and was not affected by concentrations within the investigated range. In cerebrospinal fluid (CSF), the highest concentrations of toloxatone were obtained within 15 min after the end of the injection. The CSF level of toloxatone was equal to that of plasma unbound toloxatone and declined at a rate similar to toloxatone in plasma. These results suggest that the toloxatone passage through the blood-brain barrier may be completed by passive diffusion. In addition, the unbound plasma concentration would accurately reflect the toloxatone concentration in CSF and could be a useful tool for drug monitoring.