Evidence of d-phenylglycine as delivering tool for improving l-dopa absorption

Journal of Biomedical Science

Research

Ming-Cheng Tsai¹  Tung-Hu Tsai²  Hsiao-Hwa Lu³  Hui-Po Wang⁴  Chun-Li Wang⁴  Yang-Bin Fan⁴ 

[1] Department of Pharmacology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Rd., Taipei, Taiwan;Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 155 Li-Nong Street, Section 2, Taipei, Taiwan;Roche Products Ltd., Taipei, Taiwan;Taipei Medical University College of Pharmacy, 250 Wu-Hsing St., 110-31, Taipei, Taiwan;

关键词: Dipeptide;    Methamphetamine;    Oral Absorption;    Cephradine;    Jejunal Segment;   

DOI  :  10.1186/1423-0127-17-71

 received in 2010-07-13, accepted in 2010-09-06,  发布年份 2010

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Wang et al; licensee BioMed Central Ltd. 2010