Distribution of gacyclidine enantiomers in spinal cord extracellular fluid

• Published in: Pharmaceutical research 2000-02, Vol.17 (2), p.148-153
• Main Authors: HOIZEY, G, KALTENBACH, M. L, DUKIC, S, LAMIABLE, D, LALLEMAND, A, D'ARBIGNY, P, MILLART, H, VISTELLE, R
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Proteins - metabolism; Catheterization; Catheters; Cyclohexanes - chemistry; Cyclohexanes - pharmacokinetics; Cyclohexenes; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacokinetics; Experiments; Extracellular Space - metabolism; Glutamatergic system (aspartate and other excitatory aminoacids); Injections, Intravenous; Laboratory animals; Male; Medical sciences; Microdialysis; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacokinetics; Pharmacology. Drug treatments; Piperidines - chemistry; Piperidines - pharmacokinetics; Plasma; Protein Binding; Rats; Rats, Wistar; Spinal cord; Spinal Cord - metabolism; Stereoisomerism
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1007557028313

Determination of the pharmacokinetics of gacyclidine enantiomers, a non-competitive NMDA antagonist, in plasma and spinal cord extracellular fluid (ECF) of rats. Implantation of microdialysis probes in spinal cord (T9). Serial collection of plasma samples and ECF dialysates over 5 hours after IV bolus administration of (+/-)-gacyclidine (2.5 mg/kg). Plasma protein binding determined in vivo by equilibrium dialysis. Chiral GC/ MS assay. Plasma concentrations of (+)-gacyclidine were approximately 25% higher than those of (-)-gacyclidine over the duration of the experiment in all animals. Plasma concentrations decayed in parallel in a biphasic manner (t1/2alpha approximately 9 min; t1/2beta approximately 90 min) with no significant difference between enantiomers. Clearance and volume of distribution of (-)-gacyclidine were approximately 20% higher than those of its optical antipode (CL: 248 vs 197 ml.kg(-1)x min(-1); Vdbeta: 31.6 vs 23.5 1/kg). Protein binding (approximately 90%) was not stereoselective. Both gacyclidine enantiomers were quantifiable in spinal cord ECF 10 min after drug administration and remained stable over the duration of the experiment in spite of changing blood concentrations. Penetration of (-)-gacyclidine was significantly higher (approximately 40%) than that of (+)-gacyclidine in all animals. Yet, exposure of spinal cord ECF was similar for both enantiomers, and not correlated with plasma AUCs. The disposition of gacyclidine enantiomers is stereoselective. Both enantiomers exhibit a high affinity for spinal cord tissue and their distribution may involve a stereoselective and active transport system. This hypothesis could also explain the discrepancy between drug concentrations in plasma and spinal cord ECE