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

Abstract

We investigated the rate of penetration into and the intra-relationship between the serum, cerebrospinal fluid (CSF) and regional brain extracellular fluid (bECF) compartments following systemic administration of lamotrigine in rat. The serum pharmacokinetics were biphasic with an initial distribution phase, (half-life approximately 3 h), and then a prolonged elimination phase of over 30 h. The serum pharmacokinetics were linear over the range 10 - 40 mg kg(-1). Using direct sampling of CSF with concomitant serum sampling, the calculated penetration half-time 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). Using in vivo recovery corrected microdialysis sampling in frontal cortex and hippocampus with concomitant serum sampling, the calculated penetration 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 total serum concentration ratio (0.40+/-0.04) was similar to the free to total serum concentration (0.39+/-0.01), and did not differ between hippocampus and frontal cortex. The species specific serum kinetics can explain the prolonged action of lamotrigine in rat seizure models. Lamotrigine has a relatively slow penetration into both CSF and bECF compartments compared with antiepileptic drugs used in acute seizures. Furthermore, the free serum drug concentration is not the sole contributor to the CSF compartment, and the CSF concentration is an overestimate of the bECF concentration of lamotrigine.

Figure 1

Serum pharmacokinetics following intraperitoneal injection of lamotrigine (LTG: 10, 20 or 40 mg kg⁻¹) in (a) rats with CSF catheters over 30 h and (b) rats with microdialysis probes compared with serum concentrations from rats with CSF catheters over 5 h. Data are presented as mean±s.e.mean of 5–6 rats. (c) Serum lamotrigine free/total concentration ratio at differing total lamotrigine concentrations demonstrating no concentration effect on lamotrigine serum protein binding. Dotted line indicates mean value of ratio.

Figure 2

(a) Cerebrospinal fluid pharmacokinetics of lamotrigine following intraperitoneal injection of lamotrigine (LTG: 10 or 20 mg kg⁻¹). Data are presented as mean±s.e.mean of 5–6 rats. (b) Lamotrigine cerebrospinal fluid:serum concentration ratio-time profile. Dotted line indicates free serum concentration ratio. Continuous line indicates modelled values (see Methods). Data are presented as mean±s.e.mean of eight rats.

Figure 3

Extracellular fluid pharmacokinetics of lamotrigine. (a) Calculation of in vivo microdialysis probe recoveries. C_out is the concentration of lamotrigine in dialysate. C_in is concentration of lamotrigine in perfusate. Slope of line through points gives recovery (−0.048±0.003), and intercept gives extracellular concentration (−15.6±1.3 μmol l⁻¹). Data are presented as mean±s.e.mean for three rats. (b) Microdialysis concentrations of lamotrigine corrected for in vivo recovery in hippocampus (HP) and frontal cortex (FC) following intraperitoneal injection of lamotrigine (LTG: 20 or 40 mg kg⁻¹). Data are presented as mean±s.e.mean of six rats. (c) Lamotrigine bECF:serum concentration ratio-time profile. Dotted line indicates free serum concentration ratio. Continuous line indicates modelled values (see Methods). Data are presented as mean±s.e.mean of eight rats.