STUDIES ON THE PHARMACOKINETICS OF ³H-NERIIFOLIN IN RATS

Neriifolin is one of the cardiac glycosides isolated from the kernel of the fruit of Thevetia neriifolia JUSS. Since the total glycoside extracted from this plant has been used clinically in heart diseases with promising results, clinical trial of neriifolin is being planned. As a prerequisite for clinical trial, the pharmacokinetics of neriifolin have been studied in rats using tritium labeled compound.Biological samples were first shaken with a small volume of petroleum ether. The aqueous layer was mechanically extracted with chloroform. After centrifugation the chloroform layer was separated and washed once with phosphate buffer(pH 7.0). An aliquat of the chloroform layer was transfered to a counting vial and evaporated to dryness. The radioactivity in the vial was quantitated in Beckman LS 9800 liquid scintillation counter after adding a toluene scintillation cocktail. The measured radioactivity was shown to be unchanged neriifolin by specificity tests using TLC technic.After intravenous injection of ³H-neriifolin 8 μCi/kg to rats, the plasma drug concentration-time curve was shown to fit a three compartment model with the following pharmacokinetic parameters: T_1/2β =5d; Vd=15.3 L/kg; Cl_γ=0.098 L/kg.h; Cl_R=0.006 L/kg.h. The concentrations of ³H-neriifolin in th eliver, bile and gastrointestinal tract were higher than those in other tissues and persisted longer. After oral administration of ³H-neriifolin 8μCi/kg to rats, absorption was shown to be rapid and complete with a bioavailability of 97.6%.Most of the administered radioactivity was excreted from the bile and feces.Within 96 h after intravenous injection, the total radioactivity excreted via the bile was 70% of the dose of which only 3～4% was unchanged drug. The total radioactivity excreted from feces accounted for 46.6% of the dose in 110 h after intravenous injection and 63.8% of the dose in 221h after oral administration. The majority of the radioactivity was found to be water-soluble or chloroform-soluble metabolites. The total radioactivity excreted via urine was only 8.5% of the dose after intravenous injection and 6% of the dose after oral administration. Of the total radioactivity, unchanged drug accounted for only 1～2% of the dose. Some radioactivity was shown to be present in the expired air.Experiments in vitro showed that ³H-neriifolin was highly bound to plasma protein.From these studies it appears that the pharmacokinetie behavior of neriifolin was similar to that of other lipophilic cardiac glycosides.