Han S S, Kim K Y, Ham S H, Sohn D H, Kim J B
College of Pharmacy, Wonkwang University, Iri city, Cheon-Buk, S-Korea.
Biol Pharm Bull. 1995 Mar;18(3):470-3. doi: 10.1248/bpb.18.470.
This experiment was performed to evaluate the usefulness of an experimental fibrosis model by bile duct ligation as a pharmacokinetic model of a disease state. First, experimental liver fibrosis was produced by bile duct ligation. At 4 weeks postoperation, a fibrotic condition was characterized by measurement of the aminoterminal procollagen type III peptide (PIIINP) level in serum, total collagen content in liver and light microscopic histology. Four weeks after bile duct ligation there was an increase in total collagen content of the liver to 430% of the initial values, accompanied by an increase of serum-PIIINP (385%). Secondly, we examined the pharmacokinetics of theophylline in the fibrotic rat induced by bile duct ligation. An i.v. dose of 8 mg of theophylline per kg of body weight was administered, and the levels of theophylline in serum were assayed by high performance liquid chromatography. The area under the serum concentration-time curve of theophylline was increased significantly in fibrotic rats compared with that of the control, and the total clearance of drug in fibrotic rats was low, averaging 22.6 mg/kg/h vs. 36.1 and 60.9 ml/kg/h in the control and the normal rat, respectively. However, the value of distribution during the beta-phase was not significantly affected by experimental liver fibrosis.
本实验旨在评估胆管结扎所致实验性纤维化模型作为疾病状态药代动力学模型的实用性。首先，通过胆管结扎制造实验性肝纤维化。术后4周，通过测定血清中III型前胶原氨基端肽（PIIINP）水平、肝脏总胶原含量及光镜组织学来表征纤维化状况。胆管结扎4周后，肝脏总胶原含量增加至初始值的430%，同时血清PIIINP升高（385%）。其次，我们研究了胆管结扎诱导的纤维化大鼠体内茶碱的药代动力学。静脉注射给予每千克体重8 mg的茶碱，通过高效液相色谱法测定血清中茶碱水平。与对照组相比，纤维化大鼠血清浓度-时间曲线下面积显著增加，且纤维化大鼠药物的总清除率较低，平均为22.6 mg/kg/h，而对照组和正常大鼠分别为36.1和60.9 ml/kg/h。然而，β期的分布值并未受到实验性肝纤维化的显著影响。
