Abstract
Backgroundl-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).Methodsd-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).ResultsThe 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%).ConclusionThe 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.
Highlights
Background lDopa (Figure 1), a dopamingenic precursor, has long been used for the treatment of Parkinson’s disease [1,2,3,4]
Amino acid l-Phe or l-dopa, dipeptide l-Gly-l-Pro or l-Gly-l-Phe, or cephradine was added for investigating the competition with d-phenylglycine-l-dopa in brush-border membrane vesicles (BBMV) uptake (Figure 2)
The BBMV uptake of d-phenylglycine-l-dopa was significantly inhibited by dipeptides l-Gly-l-Pro (***p < 0.001), l-Gly-l-Phe (**p < 0.01) and cephradine, a typical Intestinal peptide transporter T1 (PepT1) substrate (***p < 0.001), while was less inhibited by l-Phe and l-dopa, suggesting that PepT1 might be involved in the uptake of this dipeptide
Summary
Dopa (Figure 1), a dopamingenic precursor, has long been used for the treatment of Parkinson’s disease [1,2,3,4]. Use of this drug was reported to have wide range of inter- and intra-patient variations in the rate and the extent of absorption [5,6]. The variation in oral bioavailability due to the Recent reports indicated that intestinal PepT1, a member of proton-coupled oligopeptide transporter system, is responsible for the absorption of a variety of diand tripeptide mimetic drugs such as amino-b-lactams [12,13,14] and ACE inhibitors [15]. The fast decarboxylation of l-dopa in peripheral circulation might be prevented or prolonged as the free amino group of l-dopa is blocked by d-phenylglycine
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