Distribution of Gacyclidine Enantiomers in Spinal Cord Extracellular Fluid

Purpose . Determination of the pharmacokinetics of gacyclidineenantiomers, a non-competitive NMDA antagonist, in plasma and spinal cordextracellular fluid (ECF) of rats. Methods . Implantation of microdialysis probes in spinal cord (T9).Serial collection of plasma samples and ECF dialysates over 5 hoursafter IV bolus administration of (±)-gacyclidine (2.5 mg/kg). Plasmaprotein binding determined in vivo by equilibrium dialysis. ChiralGC/MS assay. Results . Plasma concentrations of (+)-gacyclidine were ∼25% higherthan those of (−)-gacyclidine over the duration of the experiment inall animals. Plasma concentrations decayed in parallel in a biphasicmanner (t 1/2 α ∼9 min; t 1/2 β ∼90 min) with no significant differencebetween enantiomers. Clearance and volume of distribution of(−)-gacyclidine were approximately 20% higher than those of its opticalantipode (CL: 248 vs 197 ml.kg −1 .min −1 ;Vd β : 31.6 vs 23.5 l/kg).Protein binding (∼90%) was not stereoselective. Both gacyclidineenantiomers were quantifiable in spinal cord ECF 10 min after drugadministration and remained stable over the duration of the experimentin spite of changing blood concentrations. Penetration of(−)-gacyclidine was significantly higher (∼40%) than that of (+)-gacyclidine inall animals. Yet, exposure of spinal cord ECF was similar for bothenantiomers, and not correlated with plasma AUCs. Conclusions . The disposition of gacyclidine enantiomers isstereoselective. Both enantiomers exhibit a high affinity for spinal cord tissueand their distribution may involve a stereoselective and active transportsystem. This hypothesis could also explain the discrepancy betweendrug concentrations in plasma and spinal cord ECF.