Effect of hypercapnia and/or hypoxemia and metabolic acidosis on kinetics and concentrations of phenytoin in the cerebrospinal fluid of conscious rabbits

Abstract

The present study was designed to determine the effect of changes m gases and pH in the blood on kinetics and passage to the cerebrospinal fluid (CSF) of phenytoin (DPH). Five groups of 6 rabbits were used, a control [with a mean partial pressure (Pa) of oxygen of 84 ± 2 (SEM) mmHg, partial pressure of carbon dioxide (PaCO 2) of 23 ± 1 mmHg and pH = 7.512 ±0.018], a second group with hypercapnia (PaCO 2 = 65 ± 3 mmHg, pH = 7.244 ± 0.008), a third group with hypoxemia (PaO 2 = 48 ± 2 mmHg), a fourth group with hypercapnia combined with hypoxemia (PaCO 2 = 72 ± 3 mmHg, PaO 2 = 51 ± 1 mmHg and pH = 7.252 ± 0.008) and a fifth group with metabolic acidosis (pH = 7.232 ± 0.011). All animals were conscious during the experiments following the administration of 10 mg/kg (i.v.) of phenytoin, hypoxemia decreased the clearance of phenytoin from 4.20 ± 0.55 to 2.65 ± 0.44 ml/min per kg ( P < 0.05) and consequently the area under the plasma concentration/time curve (AUC) for phenytoin increased (2575 ±319 to 4316± 740 μg min/ml; P < 0.05). Metabolic acidosis increased the volume of distribution of phenytoin from 780 ± 70 to 1103 ± 65 ml/kg ( P < 0.01). The protein binding of phenytoin was not affected by any of the experimental conditons. Finally, hypercapnia, hypoxemia and hypercapnia, combined with hypoxemia, tended to decrease the ratio of CSF to plasma concentrations of phenytoin by 26, 43 and 37% respectively; however only in the case of hypoxemia was this decrease significant ( P < 0.05). Metabolic acidosis tended to increase this ratio by 33%. It was concluded that changes in blood gases and pH did alter the kinetics of phenytoin, which may result in changes in the anticonvulsant effect of phenytoin.