| Summary: | 博士 === 臺北醫學大學 === 藥學系(博士班) === 96 === The purpose of this study was to investigate the drug interaction between caffeic acid and L-dopa. Both caffeic acid and L-dopa/carbidopa were simultaneously administered to rabbits via an intramuscular (IM) injection.
First, the dose-dependent pharmacokinetics of levodopa (L-dopa) was studied in rabbits via an intramuscular administration. Three different doses of L-dopa/carbidopa (2/0.5, 5/1.25, and 10/2.5 mg•kg-1) were administered to six male rabbits via an IM route, and one dose of L-dopa/carbidopa (2/0.5 mg•kg-1) was administered via an intravenous (IV) route with a washout period of 1-week between different doses in a crossover treatment protocol. Plasma samples were collected after each treatment and the concentrations of L-dopa and 3-O-methyldopa (an L-dopa metabolite, 3-OMD) were measured by a sensitive high-performance liquid chromatographic (HPLC) method. Subsequently, these measurements were used to determine the pharmacokinetic behavior of L-dopa and 3-OMD. The results indicated that the absorption of L-dopa was fast with the time to the peak within 30 min, but the formation of 3-OMD was slow with the time to the peak of 120-180 min after IM administration. The IM bioavailability of L-dopa was in the range of 0.70-1.21, and the relative ratios of the formation of 3-OMD at different doses of L-dopa were in the range of 0.79-1.24. No statistically significant difference could be observed for IM bioavailability of L-dopa or for the relative ratios of the formation of 3-OMD in this dose range. The elimination half-lives of L-dopa and 3-OMD also exhibited no significant differences for each dose after IM administration. In addition, both the area under the curve (AUC) and maximum plasma concentration (Cmax) values of L-dopa and 3-OMD increased proportionally over the dose range of 2/0.5–10/2.5 mg•kg-1 for L-dopa/carbidopa, suggesting that L-dopa and 3-OMD obeyed dose-independent pharmacokinetics.
The impacts of caffeic acid on the pharmacokinetics of L-dopa were studied in rabbits. A single dose of 5/1.25 mg•kg-1 L-dopa/carbidopa was administered alone or was co-administered with three different doses of caffeic acid (2.5, 5, and 10 mg•kg-1), or a single dose of 5 mg•kg-1 caffeic acid was administered alone via an IM route to six rabbits each in a crossover treatment protocol. Plasma levels of L-dopa, 3-O-methyldopa (3-OMD), caffeic acid, and ferulic acid were determined and subsequently used to calculate their pharmacokinetic parameters. The results indicated that caffeic acid administered at a dose of 10 mg•kg-1 decreased about 22% of the peripheral formation of 3-OMD and about 31% of the Cmax of 3-OMD. In addition, the metabolic ratios (MR, AUC of 3-OMD/AUC of L-dopa) decreased by about 22%. Results also indicated that caffeic acid significantly decreased the proportion of 3-OMD (p < 0.05). In contrast, the parameters of neither caffeic acid nor ferulic acid were significantly affected by L-dopa/carbidopa. In conclusion, caffeic acid at a dose of 10 mg•kg-1 can significantly affect the COMT metabolic pathway of L-dopa.
When L-dopa/carbidopa and caffeic acid were simultaneously administered, plasma level of L-dopa was increased. Due to large variance, the value did not show statistically significant differences. Therefore, to evaluate the effect of caffeic acid in higher dose with L-dopa, the investigation was carried out. In addition, L-dopa/carbidopa was simultaneously administered with other polyphenols including dihydrocaffeic acid and catechin to evaluate the drug interactions between L-dopa and dihydrocaffeic acid or catechin. A single dose of 5/1.25 mg•kg-1 L-dopa/carbidopa was administered alone or L-dopa/carbidopa was co-administered with high dose (50 mg•kg-1) of three different compounds including caffeic acid, dihydrocaffeic acid (DHCA) and catechin via an IM route to six rabbits each in a crossover treatment protocol. Plasma levels of L-dopa, 3-O-methyldopa (3-OMD), and carbidopa were determined and subsequently used to calculate their pharmacokinetic parameters. The results indicated that AUC0-t, AUC0-?V and Cmax values of L-dopa were more than the values of L-dopa after administered L-dopa alone. These data were all show statistically significant differences (p < 0.05) except the Cmax values of L-dopa for co-administered with catechin. DHCA affected L-dopa availability the most among these compounds. The AUC0-t, AUC0-?V and Cmax values of L-dopa were all increased 64%, 64% and 68%, respectively. After all treatments, AUC0-t, AUC0-?V and Cmax values of 3-OMD were less than the values of 3-OMD after administered L-dopa alone. These difference were all show statistically significant differences (p < 0.05) except the AUC0-t, AUC0-?V and Cmax values of 3-OMD for co-administered with caffeic acid. Catechin affected 3-OMD data the most among these compounds. The AUC0-t , AUC0-?V and Cmax values of 3-OMD were all decreased 65%, 64% and 64%, respectively. Besides, catechin reduced metabolic ratio of 3-OMD to 76%.
Because catechin affects L-dopa metabolism by COMT pathway the most among these compounds, it intrigues us to advance investigation whether still exists drug interaction between the lower dose of catechin and L-dopa. A single dose of 5/1.25 mg•kg-1 L-dopa/carbidopa was administered alone or L-dopa/carbidopa was co-administered with three different doses of catechin (10, 20, and 50 mg•kg-1) via an IM route to six rabbits each in a crossover treatment protocol. Plasma levels of L-dopa, 3-OMD, carbidopa and catechin were determined and subsequently used to calculate their pharmacokinetic parameters. The results indicated that L-dopa was co-administered with three different doses, AUC0-t , AUC0-?V and Cmax values of L-dopa were more than the values of L-dopa after administered L-dopa alone. These data were show statistically significant differences (p < 0.05) except the Cmax values of L-dopa for co-administered with catechin (50 mg•kg-1). Catechin (20 mg•kg-1) affected L-dopa availability the most among these compounds. The AUC0-t , AUC0-?V and Cmax values of L-dopa were increased 78%, 83% and 82%, respectively. After all treatments, AUC0-t, AUC0-?V and Cmax values of 3-OMD were less than the values of 3-OMD after administered L-dopa alone. These differences all were show statistically significant differences (p < 0.05). 50 mg•kg-1 of catechin affected 3-OMD data the most among these doses. After co-administered with 10, 20 and 50 mg•kg-1 of catechin, the metabolic ratio mean of 3-OMD was decreased 56%, 68% and 76%, respectively. The effects were dependent on catechin doses.
From the above studies, we inferred that PD patients simultaneously received L-dopa and beverage or fruits containing polyphenols, the polyphenols would inhibit L-dopa metabolism by COMT pathway. Therefore, polyphenols would enhance L-dopa bioavailability and reduce 3-OMD formation, and then increased L-dopa response for PD treatment.
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