D-苯甘氨酸作为提高 L-多巴吸收的传递工具的证据。

Evidence of D-phenylglycine as delivering tool for improving L-dopa absorption.

机构信息

Taipei Medical University College of Pharmacy, 250 Wu-Hsing St,, Taipei, 110-31, Taiwan.

出版信息

J Biomed Sci. 2010 Sep 6;17(1):71. doi: 10.1186/1423-0127-17-71.

DOI:10.1186/1423-0127-17-71

PMID:20815935

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2941486/

Abstract

BACKGROUND

L-dopa has been used for Parkinson's disease management for a long time. However, its wide variety in the rate and the extent of absorption remained challenge in designing suitable therapeutic regime. We report here a design of using D-phenylglycine to guard L-dopa for better absorption in the intestine via intestinal peptide transporter I (PepT1).

METHODS

D-phenylglycine was chemically attached on L-dopa to form D-phenylglycine-L-dopa as a dipeptide prodrug of L-dopa. The cross-membrane transport of this dipeptide and L-dopa via PepT1 was compared in brush-boarder membrane vesicle (BBMV) prepared from rat intestine. The intestinal absorption was compared by in situ jejunal perfusion in rats. The pharmacokinetics after i.v. and p.o. administration of both compounds were also compared in Wistar rats. The striatal dopamine released after i.v. administration of D-phenylglycine-L-dopa was collected by brain microdialysis and monitored by HPLC. Anti-Parkinsonism effect was determined by counting the rotation of 6-OHDA-treated unilateral striatal lesioned rats elicited rotation with (+)-methamphetamine (MA).

RESULTS

The BBMV uptake of D-phenylglycine-L-dopa was inhibited by Gly-Pro, Gly-Phe and cephradine, the typical PepT1 substrates, but not by amino acids Phe or L-dopa. The cross-membrane permeability (Pm*) determined in rat jejunal perfusion of D-phenylglycine-L-dopa was higher than that of L-dopa (2.58 ± 0.14 vs. 0.94 ± 0.10). The oral bioavailability of D-phenylglycine-L-dopa was 31.7 times higher than that of L-dopa in rats. A sustained releasing profile of striatal dopamine was demonstrated after i. v. injection of D-phenylglycine-L-dopa (50 mg/kg), indicated that D-phenylglycine-L-dopa might be a prodrug of dopamine. D-phenylglycine-L-dopa was more efficient than L-dopa in lowering the rotation of unilateral striatal lesioned rats (19.1 ± 1.7% vs. 9.9 ± 1.4%).

CONCLUSION

The BBMV uptake studies indicated that D-phenylglycine facilitated the transport of L-dopa through the intestinal PepT1 transporter. The higher jejunal permeability and the improved systemic bioavailability of D-phenylglycine-L-dopa in comparison to that of l-dopa suggested that D-phenylglycine is an effective delivery tool for improving the oral absorption of drugs like L-dopa with unsatisfactory pharmacokinetics. The gradual release of dopamine in brain striatum rendered this dipeptide as a potential dopamine sustained-releasing prodrug.

摘要

背景

左旋多巴已被用于治疗帕金森病很长时间。然而，其吸收速度和程度的多样性在设计合适的治疗方案方面仍然是一个挑战。我们在此报告一种使用 D-苯甘氨酸来保护左旋多巴通过肠肽转运体 I（PepT1）在肠道中更好吸收的设计。

方法

通过化学方法将 D-苯甘氨酸连接到左旋多巴上，形成 D-苯甘氨酸-L-多巴作为左旋多巴的二肽前体药物。在从大鼠肠道制备的刷状边界膜囊泡（BBMV）中比较了该二肽和左旋多巴通过 PepT1 的跨膜转运。通过在大鼠原位空肠灌流比较了肠道吸收。还在 Wistar 大鼠中比较了两种化合物静脉注射和口服给药后的药代动力学。通过脑微透析收集静脉给予 D-苯甘氨酸-L-多巴后纹状体中释放的多巴胺，并通过 HPLC 监测。通过计数 6-OHDA 处理的单侧纹状体损伤大鼠用（+）-甲基苯丙胺（MA）诱发的旋转来确定抗帕金森病作用。

结果

D-苯甘氨酸-L-多巴的 BBMV 摄取被 Gly-Pro、Gly-Phe 和头孢拉定抑制，这是 PepT1 的典型底物，但不受苯丙氨酸或左旋多巴的抑制。在大鼠空肠灌注 D-苯甘氨酸-L-多巴的跨膜渗透率（Pm*）高于左旋多巴（2.58±0.14 比 0.94±0.10）。D-苯甘氨酸-L-多巴在大鼠中的口服生物利用度是左旋多巴的 31.7 倍。静脉注射 D-苯甘氨酸-L-多巴（50mg/kg）后，纹状体多巴胺的释放呈持续释放谱，表明 D-苯甘氨酸-L-多巴可能是多巴胺的前体药物。与左旋多巴相比，D-苯甘氨酸-L-多巴在降低单侧纹状体损伤大鼠的旋转方面更有效（19.1±1.7%比 9.9±1.4%）。

结论

BBMV 摄取研究表明，D-苯甘氨酸促进了 L-多巴通过肠道 PepT1 转运体的运输。与左旋多巴相比，D-苯甘氨酸-L-多巴在空肠中的渗透性更高，全身生物利用度得到改善，表明 D-苯甘氨酸是改善左旋多巴等药代动力学不理想的药物口服吸收的有效递送工具。脑纹状体中多巴胺的缓慢释放使这种二肽成为一种潜在的多巴胺持续释放前体药物。