Systemic and brain bioavailabilities of D-Phenylglycine-L-Dopa, a sustained dopamine-releasing prodrug

Chun Li Wang, Yang Bin Fan, Shi En Lee, Jang Feng Lian, Jing Ping Liou, Hui Po Wang

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

D-Phenylglycine-L-Dopa (D-PhG-L-Dopa), designed as a dipeptide mimetic prodrug of dopamine, has been proven to have 31-fold higher oral bioavailability than L-Dopa in rats. To further investigate if this dipeptide enters the brain, a single-dose pharmacokinetic study by i.v. administration, in comparison with L-Dopa, was conducted to monitor brain availability. The dopamine level in the brain was also determined. The results indicated that both D-PhG-L-Dopa and L-Dopa entered the brain rapidly (Tmax 1 minute) with similar degrees of penetration (AUCbrain/AUCplasma 8.83% vs. 7.61%). As D-PhG-L-Dopa had higher systemic exposure than L-Dopa (AUC plasma 23.79 μmol·min/mL vs. 12.09 μmol·min/mL), it thus had higher brain availability (AUC brain 2.0 μmol·min/mL vs. 0.92 μmol·min/mL). Although the AUCbrain dopamine after D-PhG-L-Dopa treatment was only 24% of that from L-Dopa treatment, it however exhibited higher anti-Parkinsonism activity than L-Dopa (reduction in rotation number 47.9 ± 5.5% vs. 27.3 ± 4.8%). Higher brain dopamine residual properties of D-PhG-L-Dopa treatment compared to L-Dopa treatment, namely 3.2 times longer MRTbrain dopamine (172.15 vs. 53.78 minutes), 10 times longer Tmax brain dopamine (30 vs. 3 minutes) and 8.36 times longer half-life (T1/2 Tmax to end (min) 112.51 vs. 13.46 minutes), may explain the result. Moreover, the long terminal half-life of brain dopamine upon D-PhG-L-Dopa treatment indicated its slow dopamine-releasing property compared with L-Dopa treatment (112.51 vs. 44.85 minutes). It is also important to note that brain dopamine level was better controlled in the D-PhG-L-Dopa group than in the L-Dopa group (Cmax/ Cmin 1.62 vs. 9.85). In conclusion, this study demonstrated that D-PhG-L-Dopa is an intrinsic dopamine-sustained-releasing prodrug. The limited concentration fluctuation of released dopamine in the brain is beneficial for the clinical management of Parkinson's disease.

Original languageEnglish
Pages (from-to)136-141
Number of pages6
JournalJournal of Food and Drug Analysis
Volume21
Issue number2
DOIs
Publication statusPublished - Jun 2013

Fingerprint

L-dopa
Prodrugs
Levodopa
dopamine
Biological Availability
bioavailability
Dopamine
brain
Brain
2-phenylglycine
dipeptides
Dipeptides
half life
Area Under Curve
Half-Life

Keywords

  • Anti-Parkinsonism activity
  • Brain homogenate
  • CNS bioavailability
  • D-Phenylglycine-L-Dopa
  • PepT1

ASJC Scopus subject areas

  • Food Science
  • Pharmacology

Cite this

Systemic and brain bioavailabilities of D-Phenylglycine-L-Dopa, a sustained dopamine-releasing prodrug. / Wang, Chun Li; Fan, Yang Bin; Lee, Shi En; Lian, Jang Feng; Liou, Jing Ping; Wang, Hui Po.

In: Journal of Food and Drug Analysis, Vol. 21, No. 2, 06.2013, p. 136-141.

Research output: Contribution to journalArticle

Wang, Chun Li ; Fan, Yang Bin ; Lee, Shi En ; Lian, Jang Feng ; Liou, Jing Ping ; Wang, Hui Po. / Systemic and brain bioavailabilities of D-Phenylglycine-L-Dopa, a sustained dopamine-releasing prodrug. In: Journal of Food and Drug Analysis. 2013 ; Vol. 21, No. 2. pp. 136-141.
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