The pharmacokinetic characteristics of ginsenoside Rh2, an anticancer nutrient, were analyzed in dogs and rats, including plasma kinetics, bioavailability, tissue distribution, plasma protein binding and excretion. The bioavailability of Rh2 is about 5% in rats and 16% in dogs. Multiple-dosing (7 days, 1 mg/kg bid) did not affect the pharmacokinetics in dogs. After oral dosing, Rh2 distributed mainly to the liver and gastrointestinal tissues in rats. In rats, the circulating fraction of Rh2 bound to plasma proteins was around 70%. The systemic clearance, however, was low -- around 2 and 20 ml/min/kg in dogs and rats, respectively. Only 1% of dosed Rh2 were recovered in excreta of rats as the intact form after oral administration, while 30% was excreted unchanged in bile after i.v. dosing. We subsequently investigated the membrane permeability of Rh2 across Caco-2 cell monolayers, stability and elimination profiles in the gastrointestinal environment. Low membrane permeability (P(app)(AP-BL): 1.91 x 10(-8)cm/s), efflux transport (efflux ratio: 9.8), pre-systemic elimination (degradation in acidic condition; metabolism in intestine tissue and contents), as well as low solubility largely accounted for the low bioavailability of Rh2. Regarding the low solubility of Rh2, micronization of the dose almost doubled the rate of absorption in dogs. Preliminary metabolite profiling confirmed the presence of the deglycosidating product protopanaxadiol in rat feces. A possible metabolite in rat bile and a potential sulfate-conjugate in rat urine were also detected.