Influence of dietary protein deficiency on the pharmacokinetics of DA-8159 and one of its metabolites, DA-8164, was investigated after intravenous and oral administration of DA-8159 at a dose of 30 mg kg(-1) to male Sprague-Dawley rats allowed free access to a 23% (control) or 5% (protein-calorie malnutrition, PCM) casein diet for 4 weeks. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of DA-8164 were significantly smaller after both intravenous (87.0 vs 162 microg min mL(-1)) and oral (144 vs 319 microg min mL(-1)) administration of DA-8159 to PCM rats. This could be due to the decrease in CYP3A1/2 (50-60%) in the rats because DA-8164 was mainly formed via CYP3A1/2 in rats. This could be supported by significantly slower in-vitro CL(int) (2.04+/-0.646 vs 3.15+/-0.693 microL min(-1) (mg protein)(-1)) for the formation of DA-8164 in hepatic microsomal fraction of PCM rats. After intravenous administration of DA-8159, the AUC values of DA-8159 were not significantly different between the two groups of rats although the AUC of DA-8164 was significantly smaller in PCM rats, and this may be due to the minor metabolic pathway of DA-8164 in rats. However, after oral administration of DA-8159, the AUC of DA-8159 was significantly greater in PCM rats (194 vs 122 microg min mL(-1)). This was not due to enhanced absorption of DA-8159 from the gastrointestinal tract in the rats but may be due to a decreased intestinal first-pass effect of DA-8159 in the rats.