In Vitro and In Vivo Evaluation of a Novel Water-Soluble N-Glycyl Prodrug (N-GLY-CBZ) of Carbamazepine

ABSTRACT The synthesis and characterization of N -glycyl-carbamazepine ( N -Gly-CBZ), an N -acyl urea derivative of carbamazepine (CBZ) designed to act as a prodrug and convert to CBZ and glycine in vivo by enzymatic cleavage of the glycyl-urea bond was recently reported. The rate and extent of conversion of N -Gly-CBZ to CBZ in a whole animal model is reported here along with supporting in vitro data. Pharmacokinetic parameters were determined for N -Gly-CBZ and CBZ following IV and oral administration of N -Gly-CBZ and CBZ control to rats using a crossover design. The in vivo elimination of N -Gly-CBZ following IV administration in rats was biphasic in nature with a t 1/2 of about 1.1 min, which was very similar to the t 1/2 for appearance of CBZ. The mean value for the relative AUC ratio for CBZ from N -Gly-CBZ and CBZ from a cyclodextrin solution showed that N -Gly-CBZ delivered a 98 ± 16% (± SD) equivalent dose of CBZ in six rats. The results of the IV dosing pharmacokinetics investigation were consistent with N -Gly-CBZ acting as a prodrug with rapid and complete conversion to CBZ in vivo . The overall absolute oral bioavailability of CBZ from N -Gly-CBZ was determined to be 41 ± 14% in three rats. The relative oral bioavailability of CBZ from N -Gly-CBZ compared to an oral CBZ control was 1.72 ± 0.54. That is, the prodrug, N -Gly-CBZ, demonstrated superior oral bioavailability of CBZ over the CBZ control, which was likely due to its greater aqueous solubility.