- 作者: Chun-Li Wang; Yang-Bin Fan; Hsiao-Hwa Lu; Tung-Hu Tsai; Ming-Cheng Tsai; Hui-Po Wang
- 作者服務機構: Taipei Medical University College of Pharmacy, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
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-ldopa
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-ldopa
was collected by brain microdialysis and monitored by HPLC. Anti-
Parkinsonism effect was determined by counting the rotation of 6-OHDAtreated
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-ldopa
(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-ldopa
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 sustainedreleasing
prodrug. - 中文關鍵字: --
- 英文關鍵字: --