• BA method development + PK pre-experiment + BA method validation
Determine a reasonable calibration range, examine the interference and stability in actual samples, and optimize the blood sampling time points (3 points near tmax at least; time points in the absorption phase, tlast>=3 *t1/2 or Clast <=1/10 Cmax)
• Routine PK experiment:
Rodent + non-rodent, lowest effective dose + medium dose + high dose, fasting before and after oral administration. For other extravascular administration routes, non-rodent IV/EV cross-over should be conducted. Select an effective dose for repeated administration, and compare the C-t curve and PK parameters of the first and last administration after reaching a steady state.
• Tissue distribution experiment:
Rodent, after selecting an effective dose for administration, take at least one-time point during plasma absorption phase, near Cmax, and elimination phase to sample heart, liver, spleen, lung, kidney, gastrointestinal tract, gonad, brain, body fat, bone and muscle and target tissues. Measure concentrations of drugs and major metabolites in both muscle and target tissues.
• Excretion test (substance balance)
Rodent, after selecting an effective dose for administration, collect urine in intervals until drug and major metabolite concentrations in samples are lower than LLOQ or less than 1% of Dose. Administer another group of via bile duct intubation collect bile in intervals. Radioisotope labeling is generally recommended and can be arranged in the clinical phase.
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