The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro-intestinal first-pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120 min. Based on the values of the kinetic constants (K(m) and V(max)), the propensity for UDPGA-dependent conjugation compared with NADPH-dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague-Dawley rats were administered kaempferol intravenously (i.v.) (10, 25 mg/kg) or orally (100, 250 mg/kg). Gastro-intestinal first-pass effects were observed by collecting portal blood after oral administration of 100 mg/kg kaempferol. Pharmacokinetic parameters were obtained by non-compartmental analysis using WinNonlin. After i.v. administration, the plasma concentration-time profiles for 10 and 25 mg/kg were consistent with high clearance (approximately 3 L/hr/kg) and large volumes of distribution (8-12 L/hr/kg). The disposition was characterized by a terminal half-life value of 3-4 h. After oral administration the plasma concentration-time profiles demonstrated fairly rapid absorption (t(max) approximately 1-2 h). The area under the curve (AUC) values after i.v. and oral doses increased approximately proportional to the dose. The bioavailability (F) was poor at approximately 2%. Analysis of portal plasma after oral administration revealed low to moderate absorption. Taken together, the low F of kaempferol is attributed in part to extensive first-pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver.