Pharmacokinetic modeling of the anticonvulsant action of phenobarbital in rats
Dingemanse, J.; van Bree, J.B.; Danhof, M.
Journal of Pharmacology and Experimental Therapeutics 249(2): 601-608
1989
ISSN/ISBN: 0022-3565 PMID: 2724142 Document Number: 329237
The aim of this study was to develop a model for the relationship between concentration and anticonvulsant effect of phenobarbital in the rat. The method of quantitating the anticonvulsant response on the basis of plasma pentylenetetrazol threshold concentations, was optimized by application of a longitudinal study design. The pharmacokinetics of phenobarbital were studied in a separate set of rats (elmination half-life 11 .+-. 2 hr). The anticonvulsant effect was measured 1 hr after i.v. administration. Concentration-effect relationships were assessed for serum (total and free), cerebrospinal fluid and brain concentrations on the basis of the sigmoid maximum effect model. The EC50 for total serum was 76 .+-. 9 mg/l and for free serum, cerebrospinal fluid and brain 44 .+-. 5, 43 .+-. 7 and 50 .+-. 8 mg/l and mg/kg, respectively (means .+-. S.E.). The maximum effect was about 120 m g/l of pentylenetrazol. The respective EC50 ratios corresponded closely with the concentration ratios between the different compartments as determined by orthogonal regression analysis. For the greater part of the concentration range the concentration-effect relationship also could be fitted accurately to a simple linear model. Such relationships were not perturbed by the occurrence of seizures as these did not alter the distribution profile of phenobarbital. The pharmacokinetics and pharmacodynamics of p-hydroxyphenobarbital, the main metabolite of phenobarbital, also were investigated. This compound is elminated very rapidly and has neither anticonvulsant activity of its own nor influences the anticonvulsant efect of phenobarbital at serum concentrations up to 30 mg/l. The described experimental strategies allow the study of factors influencing the concentration-anticonvulsant effect relationship of phenobarbital.