Local absorption kinetics into the portal system using the portal-venous concentration difference after an oral dose of diclofenac in the awakening rat. Accelerative effect of bile on intestinal absorption of diclofenac.
The local absorption kinetics from the intestinal tract into the portal system was evaluated using the portal-venous concentration difference (P-V difference) after oral administration of diclofenac in conscious rats. The local absorption ratio (Fa), mean local absorption time (ta), and relative variance (sigma 2/ta2) from the intestinal tract into the portal system were estimated by simultaneously measuring the portal and venous concentrations, using diclofenac as a model drug. The effect of bile on diclofenac intestinal absorption was also investigated. The awakening rats simultaneously cannulated into the jugular and portal veins were divided into group A with intact enterohepatic circulation (EHC) and into another group with bile-duct cannulation to block EHC. The rats in the latter group were further divided into group B without the bile supply to the intestinal tract and into group C with the bile supply from the other rat. After oral administration of diclofenac to rats in groups A, B, and C, the portal and venous concentrations of diclofenac in each rat were simultaneously monitored by HPLC method at proper time intervals. The absorption time profile of diclofenac into the portal system was directly predicted from P-V difference. Plasma concentrations of diclofenac in the portal vein were constantly higher than those in the jugular vein after the oral administration. It was demonstrated that P-V difference was caused by absorption from the intestinal tract into the portal system. Fa in groups A, B, and C were estimated to be 91.5% for 8 hr, 33.8% for 3 hr, and 57.8% for 3 hr, respectively. ta in groups A, B, and C were estimated to be 2.26 hr, 0.65 hr, and 0.96 hr, respectively. sigma 2/ta2 in groups A, B, and C were 1.31, 0.48, and 0.55, respectively. Fa and ta of diclofenac extensively increased in the presence of the bile in the intestinal tract, whereas sigma 2/ta2 was unaffected by the bile. The mean absorption time (MAT) almost agreed with ta, which demonstrates that the mean transit time through the liver (tH) is negligible in MAT(= ta+tH).
Tabata
K
K
Faculty of Pharmaceutical Science, Kyoto University, Japan.
Yamaoka
K
K
Fukuyama
T
T
Nakagawa
T
T
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism*; D004008:Diclofenac / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D008297:Male; D011169:Portal Vein; D051381:Rats; D017208:Rats, Wistar; D014680:Veins
D004008:Diclofenac