Effects of Acute Phase Response on Pharmacokinetics of Drugs in Dogs

急性期反应对狗体内药物药代动力学的影响

• 批准号: 10839006
• 负责人: SHIMODA Minoru
• 金额: $ 2.05万
• 依托单位: Tokyo University of Agriculture and Technology
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10839006/
• 关键词: dogs; acute phase response; metabolism; cytochrome P450; チトクロームP450; ニフェジピン; テオフェリン

This study examined effect of acute phase response on drug disposition in dogs. Total body clearance (CLtot) of antipyrine was decreased to 60% by the acute phase response induced by lipopolysuccharide (LPS) injection. The activities of several cytochrome P450 (CYP) subfamilies (CYP2C, 2D and 3A) from hepatic microsomes of LPS treated dogs were about a half of those of non-treated dogs. Michaelis-Menten kinetic analysis indicated that this decrease is due to a decrease in amounts of these CYPs. The decreases in CYP activities were also examined by in vivo experiments. Theophyline, phenytoin and nifedipine, which are eliminated from the body by the metabolism catalyzed by CYP1A, 2C and 3A, respectively, showed about a half decrease in their CLtot after LPS treatment. It is, therefore, indicated that acute phase response may result in a substantial decrease in several CYP activities and this decrease may substantially affect drug disposition even in a clinical situation. This was demonstrated by the experiment where effects of acute phase response on nifedipine pharmacokinetics after oral administration to dogs. Bioavailability of nifedipine after LPS treatment was almost twice, compared with that before treatment. In conclusion, acute phase response may substantially alter drug disposition in dogs even in clinical situations. Therefore, dosage regimen must be altered in such conditions of dogs. This study suggests that dose should be decreased to about a half of recommended doses, if drugs mainly eliminated by CYP-dependentmetabolism.

本研究检查了犬急性期反应对药物处置的影响。注射脂多糖（LPS）诱导的急性期反应使安替比林的总清除率（CLtot）下降至60%。LPS处理犬肝微粒体细胞色素P450（CYP）亚家族（CYP 2C、2D和3A）的活性约为未处理犬的一半。Michaelis-Menten动力学分析表明，这种减少是由于这些CYP的量减少。还通过体内实验检查了抗肿瘤活性的降低。茶碱、苯妥英和硝苯地平分别通过CYP 1A、2C和3A催化的代谢从体内消除，在LPS处理后显示其CLtot降低约一半。因此，表明急性期反应可能导致几种药物活性的显著降低，这种降低可能会显著影响药物处置，即使在临床情况下。这一点已通过犬口服硝苯地平后急性期反应对药代动力学的影响实验得到证实。硝苯地平经LPS处理后的生物利用度约为处理前的2倍。总之，即使在临床情况下，急性期反应也可能显著改变犬中的药物分布。因此，在犬的这种情况下，必须改变给药方案。本研究表明，如果药物主要通过CYP代谢消除，则剂量应减少至推荐剂量的一半左右。