Effects of Acute Phase Response on Pharmacokinetics of Drugs in Dogs

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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.