| Summary: | 博士 === 台北醫學院 === 藥學研究所 === 87 === Pharmacokinetics and metabolism of caffeic acid (3,4-dihydrocinnamic acid, CA) were studied using rabbits as animal model. To the beginning, linear pharmacokinetics of CA was studied. Three different doses (5, 10 and 25 mg/kg) were administered intravenously (IV) to six rabbits, respectively. The concentration-time profiles for CA could be fitted by a two compartment model for each dose. The results showed that total body clearance (CLtotal) and elimination rate constant from the central compartment (k10) after a 5 mg/kg dose were greater than those after the other two doses. Furthermore, the *-half life and mean residence time (MRT) after a 5 mg/kg dose were less than after the other doses. The AUC value increased linearly with dose within the range of 10 mg/kg to 25 mg/kg. Most of the unchanged caffeic acid was excreted in the urine within 2 hours. The percentages of unchanged caffeic acid excreted in the urine were 63.3, 60.0 and 55.4 (%) after doses of 5, 10 and 25 mg/kg, respectively, which was not significantly different. However, significant differences in the renal clearances (CLr) and renal excretion rate constant were observed with a 5 mg/kg dose compared to the other doses. On the other hand, nonrenal clearances (CLnr) and nonrenal excretion rate constants showed no dose related differences. The differences observed in CLtotal, k10, *-half life and MRT between a 5 mg/kg dose and the other doses could be explained on the basis of the differences in renal clearance and renal excretion rate constant. After oral administration CA to rabbits, the concentration-time profiles of caffeic acid showed a double peak phenomenon. The pharmacokinetic parameters of the CLtotal, CLr, CLnr, and absorption phase half-life showed no significant differences for each dose after oral administration. These results indicated that CA showed linear pharmacokinetics after oral administration in the dose range of 5and 25 mg/kg. The results also showed that the values of the AUC and Cmax increased linearly with a dose in the range of 5 mg/kg to 25 mg/kg. The absolute bioavailability values of CA were 0.364, 0.379 and 0.402, and the percentages of unchanged CA excreted in the urine were 23.2, 22.7 and 22.0 (%) after doses of 5, 10 and 25 mg/kg, respectively. There were no significant differences obtained for absolute bioavailability and also for percentages of unchanged CA excreted in the urine in these dose ranges. After intraperitoneal administration (IP, 10 mg/kg), the concentration-time profiles of CA also showed a double peak phenomenon. The absolute bioavailability value of CA were 0.729 and the percentages of unchanged CA excreted in the urine were 43.8 (%). The calculated gastrointestinal (GI) and hepatic extraction were 0.470 and 0.271, respectively. Ratio of GI to hepatic extraction was 2.5 and showed GI eliminated CA more active than liver. Glucuronidation (CA-G) and sulfation (CA-S) of CA excreted in rabbit urine were determined enzymatically. The results showed that percentages of total CA (unchanged CA + CA-G + CA-S) excreted in the urine were 73.8 and 71.8 (%) after IV dosing (5 & 10 mg/kg), respectively. After oral dosing (5 & 10 mg/kg), percentages of total CA excreted in the urine was 37.1% and 35.6 (%), respectively. The percentages of conjugation for CA (CA-conjugation) were 10.5 and 11.9 (%), CA-G were 3.41 and 6.57 (%), and CA-S were 7.06 and 5.30 (%) after IV administration 5 and 10 mg/kg dose, respectively. After oral administration, the percentages of CA-conjugation were 13.8 and 13.3 (%), CA-G were 3.68 and 8.05 (%), and CA-S were 10.1 and 5.27 (%) for 5 and 10 mg/kg dose, respectively. There were no significant differences for percentages of total and conjugation CA excreted in the urine, for both doses neither IV nor oral. In addition, there were no significant differences for percentages of CA-conjugation excreted in the urine between administration routes for each dose. However, the percentages of CA-G showed significant differences between doses, not only for IV administration but also for oral administration. There was a linear relationship between the percentages of CA-G and doses for both IV and oral administration. It indicated that glucuronidation of CA showed dose-dependent. The ratio of CA-G/CA-S increased with dose and showed significant differences between doses for both IV and oral administration. The results indicated that sulfation of CA showed high affinity and low capacity, and glucuronidation of CA showed low affinity and high capacity, not only after IV but also after oral administration. The relative fraction of CA-conjugation/unchanged CA for oral administration was greater than that after IP administration and showed significant differences. The result indicated that the contribution of GI in CA conjugation was higher than that of liver. After IV administration of CA at dose 25 mg/kg, there was a blood to plasma concentration ratio for CA concentration at 0.710. The blood to plasma concentration ratio was concentration independent and erythrocyte to plasma concentration ratio, too. After intraduodenal administration or oral administration following bile duct cannulation, the concentration-time profiles of CA showed a double peak phenomenon. The biliary excretion of CA was less than 0.1 %. These results indicated that the reasons for concentration-time profiles of CA showed a double peak phenomenon after oral administration were not resulting from gastric emptying variability and enterohepatic circulation. However, this was likely due to the poor water solubility of CA. The metabolic pathways of CA were investigated with LC/MS/MS. It showed the sulfation of CA was predominant both in rabbit plasma and bile. Isoferulic acid and ferulic acid, methylation of CA, were found in plasma. In addition, a phase I oxidative metabolite, esculetin, was found in plasma but not in urine and bile. In urine, there were 7 metabolites identified. They included methylation of CA at 4-hydroxy group (isoferulic acid), sulfation at 3- or 4-hydroxy group of CA (CA-3-O-sulfate and CA-4-O-sulfate), methylation at 4-hydroxy group and sulfation at 3-hydroxy group (CA-4-O-methyl, 3-O-sulfate), glucuronidation at 4-hydroxy group (CA-4-O-glucuronide), and methylation either 3- or 4-hydroxy group and then glucuronidation at carboxylic acid group (Glucuronyl 3-O-methyl-CA and Glucuronyl 4-O-methyl-CA).
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