Ito T, Yamaoka K, Nakagawa T
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
J Pharm Pharmacol. 1997 Dec;49(12):1189-94. doi: 10.1111/j.2042-7158.1997.tb06068.x.
A new method has been developed for simultaneous evaluation of local absorption from the intestine into the portal system and local disposition through the liver, and for assessment of the bioavailability of a drug in a single conscious rat. The method is based on the difference between plasma concentrations in portal and systemic blood (PS method). Because cephalexin is known to be absorbed completely from the intestine and not to be eliminated through the liver, it was used as test drug to confirm the validity of the new method. The portal vein and the femoral artery of a rat were simultaneously cannulated and blood samples were obtained from both sites. Two methods of administration, single-dosing and double-dosing, were investigated and the efficacy of double-dosing (DD) was demonstrated. Rats received an intra-arterial (group A) or oral (group B) dose in single-dosing, whereas rats used for double-dosing received an oral dose 3 h after an intra-arterial dose (group C). After administration of cephalexin, the portal and arterial plasma concentrations were determined by HPLC. Groups A and B were monitored for 4 h and group C for 8 h. The portal-blood flow rate was measured by means of an electromagnetic flow-meter. Global and local moments were calculated by trapezoidal integration with extrapolation to infinite time. On the basis of the PS method, the local absorption ratio (Fa) and the mean local absorption time (t(a)) were estimated to be 0.975 +/- 0.104 and 2.19 +/- 0.51 h, respectively, in group B. By comparing the averaged moments between groups A and B, the extent of bioavailability (F), the mean absorption time (MAT) and the hepatic recovery ratio (FH) were calculated to be 1.01, 1.92 h and 1.04, respectively. The mean hepatic transit time (tH) was negligible. In group C, Fa = 0.936 +/- 0.107, tH = 1.55 +/- 0.32 h, F = 1.08 +/- 0.07, MAT = 1.55 +/- 0.40 h and F(H) = 1.17 +/- 0.14 h, the mean values being close to those from groups A and B. In conclusion, the PS method with short-period double-dosing (PS-DD method) can offer an effective means of evaluating the local absorption kinetics of drugs, because F, MAT and F(H) are obtained from a single conscious rat, and consequently the standard deviations of the quantities can be quickly estimated.
已开发出一种新方法，可同时评估药物从肠道吸收进入门静脉系统的局部吸收情况以及经肝脏的局部处置情况，并可评估清醒大鼠体内药物的生物利用度。该方法基于门静脉血与体循环血中血浆浓度的差异（PS法）。由于已知头孢氨苄可完全从肠道吸收且不经肝脏消除，因此将其用作测试药物以确认新方法的有效性。将大鼠的门静脉和股动脉同时插管，并从这两个部位采集血样。研究了单剂量给药和双剂量给药两种给药方法，并证明了双剂量给药（DD）的有效性。单剂量给药时，大鼠接受动脉内给药（A组）或口服给药（B组），而用于双剂量给药的大鼠在动脉内给药后3小时接受口服给药（C组）。给予头孢氨苄后，通过高效液相色谱法测定门静脉和动脉血浆浓度。A组和B组监测4小时，C组监测8小时。通过电磁流量计测量门静脉血流速度。通过梯形积分并外推至无限时间来计算整体矩和局部矩。基于PS法，B组的局部吸收比（Fa）和平均局部吸收时间（t(a)）分别估计为0.975±0.104和2.19±0.51小时。通过比较A组和B组的平均矩，计算出生物利用度（F）、平均吸收时间（MAT）和肝脏回收率（FH）分别为1.01、1.92小时和1.04。平均肝脏转运时间（tH）可忽略不计。在C组中，Fa = 0.936±0.107，tH = 1.55±0.32小时，F = 1.08±0.07，MAT = 1.55±0.40小时，FH = 1.17±0.14小时，这些平均值与A组和B组的平均值接近。总之，短周期双剂量给药的PS法（PS-DD法）可提供一种评估药物局部吸收动力学的有效手段，因为F、MAT和FH可从一只清醒大鼠获得，因此可快速估计这些量的标准差。
