Effects of Acute Phase Response on Pharmacokinetics of Drugs in Dogs

本研究考察了犬急性期反应对药物处置的影响。脂多糖（LPS）急性期反应使安替比林的全身清除率（CLtot）降至60%。LPS处理犬肝小体中细胞色素P450 （CYP）亚家族（CYP2C、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CYPs的数量减少。体内实验也检测了CYP活性的降低。茶碱、苯妥英和硝苯地平分别由CYP1A、2C和3A催化代谢排出体外，经LPS处理后其CLtot下降约一半。因此，表明急性期反应可能导致几种CYP活性的显著降低，这种降低甚至可能在临床情况下显著影响药物处置。这是通过实验证明，急性期反应对口服给药后硝苯地平药代动力学的影响。LPS治疗后硝苯地平的生物利用度几乎是治疗前的2倍。总之，即使在临床情况下，急性期反应也可能大大改变狗的药物处置。因此，在这种情况下，必须改变给药方案。本研究表明，如果药物主要通过cypp依赖性代谢消除，则剂量应减少至推荐剂量的一半左右。

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.