The effects of different rates of protein diet on the cythochrome P450 2D activity in healthy dogs

Abstract

Dietetic treatment is one of the important therapies in veterinary medicine. Especially in cardiovascular and kidney diseases, low-protein diet is suggested to be beneficial in minimizing their clinical signs. It is reported in human that high-protein diet activates cytochrome P450 (CYP) which is an important enzyme for metabolism of xenobiotics. In a preclinical study, hepatic CYP activity was decreased when low-protein diet was given to rats. In dogs, however, there is little information about the relationship between protein intake and CYP activities. In the present study, we clarified whether dietary protein affected activity of CYP2D, one of the responsible isozymes in metabolism of many drugs. Although it has been clarified that propranolol is metabolized by CYP2D in human liver, there is no information about the responsive CYP that metabolizes propranolol in dogs. Thus, we first clarified by chemical inhibition method using hepatic microsome that propranolol is metabolized by CYP2D also in canine liver. Then, one of the 3 diet with different rates of protein (low: 12.3%, middle: 25.3%, high: 40.1%) was given repeatedly to 7 Beagles and propranolol was administered intravenously to analyze CYP2D activity. This study was conducted in a cross over design. The plasma concentrations of propranolol were determined using a high performance liquid chromatography. The pharmacokinetic parameters of propranolol were analyzed by non-compartment model. When dog was given with middle- and high-protein diet, the values of area under the concentration of propranolol were low and the clearance was high when compared to those with low-protein diet. These data suggest that dietary protein may affect CYP2D activity in dogs.