Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine

1 We investigated the rate of penetration into and the intra-relationship b etween the serum, cerebrospinal fluid (CSF) and regional brain extracellula r fluid (bECF) compartments following systemic administration of lamotrigin e in rat. 2 The serum pharmacokinetics were biphasic with an initial distribution pha se, (half-life approximately 3 h), and then a prolonged elimination phase o f over 30 h. The serum pharmacokinetics were linear over the range 10-40 mg kg(-1). 3 Using direct sampling of CSF with concomitant serum sampling, the calcula ted penetration halftime into CSF was 0.42 +/- 0.15 h. At equilibrium, the CSF to total serum concentration ratio (0.61 +/- 0.02) was greater than the free to total serum concentration (0.39 +/- 0.01). 4 Using in vivo recovery corrected microdialysis sampling in Frontal cortex and hippocampus with concomitant serum sampling, the calculated penetratio n half-time of lamotrigine into bECF, 0.51 +/- 0.11 h, was similar to that for CSF and was not area or dose dependent. At equilibrium, the bECF to tot al serum concentration ratio (0.40 +/- 0.04) was similar to the free to tot al serum concentration (0.39 +/- 0.01), and did not differ between hippocam pus and frontal cortex. 5 The species specific serum kinetics can explain the prolonged action of l amotrigine in rat seizure models. Lamotrigine has a relatively slow penetra tion into both CSF and bECF compartments compared with antiepileptic drugs used in acute seizures. Furthermore, the free serum drug concentration is n ot the sole contributor to the CSF compartment, and the CSF concentration i s an overestimate of the bECF concentration of lamotrigine.