Kinetics of Penetration of Common Antiepileptic Drugs into Cerebrospinal Fluid

Abstract

The rate of entry of common antiepileptic drugs and some active metabolites into cerebrospinal fluid (CSF) was studied in anesthetized dogs from which blood and CSF samples were withdrawn at short intervals. Diazepam, its active metabolites desmethyldiazepam and oxazepam, clonazepam, and ethosuximide entered the CSF very rapidly with mean half-times to equilibrium between 3 and 7 min. Valproic acid, phenytoin, phenobarbital, and carbamazepine went in more slowly, but mean penetration half-times were still only 12-18 min. Primidone, its metabolite phenylethylmalondiamide , and the active metabolite of carbamazepine, i.e., carbamazepine-10,11-epoxide, passed into CSF considerably slower, with half-times of 40-50 min. In order to evaluate to what extent physicochemical properties determine the penetration rates of antiepileptic drugs into the CSF, three factors were examined: the degree of ionization of the respective drugs at physiologic pH, the plasma protein binding, and the lipid-solubility, measured by organic solvent/buffer distribution ratios. Ionization was not considered as a rate-limiting factor, because all compounds except valproic acid were highly non-ionized at pH 7.4. No correlation was found between penetration rates and plasma protein binding, but at equilibrium, the ratio between CSF and total plasma concentrations was almost equal to the free fraction of drug in plasma. A significant correlation was found between penetration rate and the benzene/buffer distribution ratio of antiepileptic drugs, which indicates that the lipid-solubility, rather than the protein binding or the degree of ionization, plays the major role in determining the differences in rate of entry of these drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood and cerebrospinal fluid pharmacokinetics of primidone and its primary pharmacologically active metabolites, phenobarbital and phenylethylmalonamide in the rat

“…4), the conversion of primidone to phenylethylmalonamide occurred earlier and also more rapidly than the conversion to phenobarbital. Thus, a rate-limiting formation of phenobarbital from primidone is suggested and confirms previous observations (34,35). Since this pattern pertains in the CSF compartment in addition, it might reasonably be concluded that, at least in the acute situation, the dosedependent anticonvulsant effect of primidone could be primarily attributable to primidone, but that phenylethylmalonamide and to a lesser extent phenobarbital also contribute (3,5,7).…”

“…The fourth study, which was undertaken in three anaesthetised dogs (6), involved serial blood and CSF sampling after injection of a single dose of primidone and phenylethylmalonamide together directly into the jejunum. One study investigated the concurrent neuropharmacokinetics of primidone in brain (3) whilst Loscher and Frey (34) used an anaesthetised dog model and reported only on the entry of primidone and phenylethylmalonamide into the CSF compartment.…”

Intravenous Carbamazepine: Comparison of Different Parenteral Formulations in a Mouse Model of Convulsive Status Epilepticus

“…The high aqueous solubility of HPPCD results in vastly improved solubility of numerous compounds, including CBZ (3,5,6). Because CBZ is nonionized at pH 7.4 and is highly lipid soluble, the drug rapidly penetrates the CNS at a rate similar to that of PHT (17). We therefore proposed that CBZ/HPPCD solutions should be ideally suited for parenteral administration to control severe epileptic attacks or SE (6), as was substantiated by the present study.…”

Role of Multidrug Transporters in Pharmacoresistance to Antiepileptic Drugs

“…By studying the rate of entry of various AEDs from blood into the CSF of anesthetized dogs, Löscher and Frey (1984) found a significant correlation between penetration rate and lipid solubility, measured by organic solvent/buffer distribution ratios, whereas the extent of plasma protein binding and degree of ionization of AEDs were of minor importance for penetration rates. These data thus substantiated that lipid solubility plays the major role in determining the difference in rate of entry of AEDs, and that AEDs, as do most centrally active drugs, penetrate into the CSF by simple diffusion.…”

“…Valproate, a branched medium-chain fatty acid, is almost completely ionized at physiologic pH, and its lipid solubility at this pH is therefore very low (Löscher and Frey, 1984). However, although it has been shown that drugs with such properties enter the CSF or brain very slowly if at all (Goldstein et al, 1974), valproate penetrated into the CSF and brain very rapidly (Löscher, 1982;Löscher and Frey, 1984). Indeed, valproate was the first AED for which an active transport in the BCB and BBB has been proposed (Frey and Löscher, 1978).…”