A FREELY MOVING AND BEHAVING RAT MODEL FOR THE CHRONIC AND SIMULTANEOUS STUDY OF DRUG PHARMACOKINETICS (BLOOD) AND NEUROPHARMACOKINETICS (CEREBROSPINAL-FLUID) - HEMATOLOGICAL AND BIOCHEMICAL-CHARACTERIZATION AND KINETIC EVALUATION USING CARBAMAZEPINE

A freely moving and behaving rat model for the chronic and simultaneous study of drug pharmacokinetics (blood) and neuropharmacokinetics [cerebrospinal fluid (CSF)] is described. The blood (jugular vein) and CSF (cisterna magna) catheters employed are simple, reliable, and inexpensive. The blood catheter was made of soft and flexible Silastic tubing and sealed with heparin. The CSF catheter consisted of intersliding polythene tubing and interlocking Silastic tubing, which allowed maneuverability within the cisternal magna space and thus prolonging patency for chronic studies. Both catheters were well tolerated by the animals, and the postoperative success rate was 80%-100%; after 8 days 80%-85% of catheters were still patent. Using a sampling protocol considered suitable for kinetic studies, we determined numerous biochemical and hematological parameters and compared them with those.values obtained postsurgically and in control rats. The parameter changes associated with the sampling protocol did not affect the kinetics of the commonly prescribed antiepileptic drug carbamazepine and its primary pharmacologically active metabolite carbamazepine-10,11-epoxide. Therefore, the model can be used to study the interrelationship between drug kinetics at central and peripheral sampling sites and mechanism(s) of drug action.