Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
J Pharm Sci. 2010 Nov;99(11):4565-75. doi: 10.1002/jps.22171.
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 (± SD) 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.
最近报道了一种卡马西平（CBZ）的 N-酰基脲衍生物 N-甘氨酰卡马西平（N-Gly-CBZ）的合成和表征，该化合物被设计为前药，通过甘氨酰-脲键的酶促裂解在体内转化为 CBZ 和甘氨酸。本文报道了在整体动物模型中 N-Gly-CBZ 转化为 CBZ 的速率和程度，并提供了支持的体外数据。采用交叉设计，在大鼠中静脉注射和口服给予 N-Gly-CBZ 和 CBZ 对照后，测定 N-Gly-CBZ 和 CBZ 的药代动力学参数。大鼠静脉注射后 N-Gly-CBZ 的体内消除呈双相性，t(1/2)约为 1.1 分钟，与 CBZ 出现的 t(1/2)非常相似。来自 N-Gly-CBZ 和来自环糊精溶液的 CBZ 的相对 AUC 比值的平均值表明，在六只大鼠中，N-Gly-CBZ 提供了（±SD）98±16%（±SD）的 CBZ 等效剂量。静脉给药药代动力学研究的结果与 N-Gly-CBZ 作为前药在体内迅速完全转化为 CBZ 的作用一致。来自 N-Gly-CBZ 的 CBZ 的总体绝对口服生物利用度在三只大鼠中确定为 41±14%。与口服 CBZ 对照相比，来自 N-Gly-CBZ 的 CBZ 的相对口服生物利用度为 1.72±0.54。也就是说，前药 N-Gly-CBZ 比 CBZ 对照具有更高的 CBZ 口服生物利用度，这可能是由于其更高的水溶解度。
