Pharmacokinetic studies on di- and tri-peptide mimetic L-Dopa analogues

• Main Authors: Lei Sai-Ian, 李世恩
• Other Authors: Hui-Po Wang
• Format: Others
• Language: zh-TW
• Published: 1999
• Online Access: http://ndltd.ncl.edu.tw/handle/45619432477421289685

碩士 === 國立臺灣大學 === 藥學研究所 === 87 === Studies indicated that an H+-coupled dipeptide-mediated carrier transport system exists in the intestines. The carrier system is responsible for the delivery of dipeptide-mimetic ACE inhibitors and the tripeptide-mimetic amino-*-lactams. D-Phenylglycine-L-Dopa (D-PhG-L-Dopa), a dipeptide mimetic dopamine derivative, was proved to be absorbed from the intestine via intestinal dipeptide transporter. Oral administration of this compound demonstrated anti-Parkinsonism activity in rats. In order to investigate if the dipeptide enters the brain, pharmacokinetic and CNS bio-availability studies on this compound after i.v. administration in rats was conducted. Single dose (100 mg/kg) of D-PhG-L-Dopa in 2.5 mL of normal saline was administered intravenously to male Wistar rats (n=6). Brains were removed and homogenized at each time point. Blood samples were withdrawn at the same time. After centrifugation, clear supernatants from both brain homogenate and plasma were subjected to alumina extraction before assay. Assay was performed on HPLC with cation exchange column coupled with electrochemical detector (10 nA, 0.75V). Pharmacokinetic parameters of L-Dopa (AUCplasma= 12.09 μmole*min/mL, AUCbrain= 0.92μmole*min/mL, Cmax in brain= 0.02±0.009μmole/mL, Tmax in brain=1 min, ) and D-PhG-L-Dopa (AUCplasma=23.79 μmole*min/mL, AUCbrain=2.10 μmole*min/mL, Cmax in brain= 0.118 ± 0.08 μmole/mL, Tmax in brain=1 min ) were compared. D-PhG-L-Dopa demonstrated higher concentrations both in plasma and in brain. The AUC of D-PhG-L-Dopa was twice to that of L-Dopa in both plasma and in brain. However the released dopamine after i.v. administration of D-PhG-L-Dopa (AUC=46.82 μg*min/mL) was five times less than that released from L-Dopa (AUC = 268.65 μg*min/mL). Since D-PhG-L-Dopa demonstrated higher anti-Parkinsonism activity than that of L-Dopa after i.v. injection, the results implied that this compound might exhibit the pharmacological effect per se or by its metabolites other than dopamine. D-phenylglycine-L-proline-L-dopa (D-PhG-L-Pro-L-Dopa) is a tripeptide mimetic dopamine derivative. Our primary in situ single-pass jejunal perfusion studies in rats revealed that, in comparison with L-Dopa, D-PhG-L-Pro-L-Dopa was much well absorbed. We thus chose this compound for oral bio-availability studies in rats. This drug was administrated i.v. and orally to male Wistar rats (n=6). Pharmacokinetic parameters (Cmax, Tmax, AUC, elimination rate constant, volume of distribution) were determined from the data of concentration- time curve with non-compartment analysis and nonlinear regression by PCNONLIN. The absolute oral bioavailability of L-Dopa and D-PhG-L-Pro-L-Dopa were 3.3% and 2.8%, respectively. As the plasma concentration of this compound was much higher than that of L-Dopa in perfusion study, this data did not correlate well with the pharmacokinetic profile. The low bioavailability of D-PhG-L-Pro-L-Dopa is probably either due to the first pass effect or due to a saturation phenomenon in perfusion study. In conclusion, this study demonstrated that the oral bio-availability of dipeptide mimetic D-PhG-L-Dopa was better than that of L-Dopa and tripeptide mimetic D-PhG-L-Pro-L-Dopa.