Effects of Acute Phase Response on Pharmacokinetics of Drugs in Dogs

本研究考察了急性时相反应对犬药物处置的影响。通过注射脂多糖(LPS)引起的急性时相反应，安替比林的整体清除率(CLtot)降至60%。细胞色素P450(CYP)的几个亚家族(细胞色素P450、2D和3A)的活性约为未处理犬的一半。Michaelis-Menten动力学分析表明，这种下降是由于这些细胞色素P450的数量减少所致。体内实验也验证了细胞色素P450活性的降低。茶碱、苯妥英钠和硝苯地平分别被CYP1A、2C和3A催化的代谢产物在体内清除后，其CLtot在脂多糖处理后下降了约一半。因此，研究表明，急性时相反应可能导致几种CYP活性的显著降低，即使在临床情况下，这种降低也可能严重影响药物的处置。急性时相反应对犬口服硝苯地平药代动力学的影响实验证明了这一点。硝苯地平在脂多糖治疗后的生物利用度几乎是治疗前的两倍。总之，即使在临床情况下，急性时相反应也可能显著改变狗的药物处置。因此，在狗的这种情况下，给药方案必须改变。这项研究建议，如果药物主要通过CYP依赖的新陈代谢消除，剂量应该减少到推荐量的一半左右。

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.