TABLE 1

Time profiles of the plasma concentrations and Kp,brain values of the six compounds in male cynomolgus monkeys after intravenous constant infusion

The male cynomolgus monkeys (fasted overnight) were fixed to monkey chairs without anesthesia during compound administration. Indinavir, quinidine, diazepam, and verapamil were intravenously infused for 3 hours at dose rates of 0.61, 0.21, 0.070, and 0.40 mg/h per kilogram, respectively, after the intravenous bolus injection of 0.50, 0.30, 0.095, and 1.2 mg/kg doses. Loperamide and paclitaxel were intravenously infused for 3 hours at dose rates of 0.20 and 0.94 mg/h per kilogram, respectively, without intravenous bolus injections. The right cerebrums were used to determine the brain-to-plasma concentration ratios (Kp,brain) at 3 hours. One cynomolgus monkey was used for each compound.

CompoundPlasma ConcentrationKp,brain
Pre2 h2.5 h3 h3 h
μMml/g brain
IndinavirBLQ0.5250.5230.5410.149
QuinidineBLQ0.4820.4900.4810.201
LoperamideBLQ0.06990.1030.08340.862
PaclitaxelBLQ0.07790.03390.03310.931
DiazepamBLQ0.08590.05520.03501.29
VerapamilBLQ0.6010.4200.4302.24
  • BLQ, below the limit of quantification; Pre, just prior to the administration of the compounds.