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

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). 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). 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%). 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.