The pharmacokinetics and cell trafficking dynamics of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (FTY720), a novel immunosuppressive agent, were examined in cynomolgus monkeys (three males and three females). After single doses of 0.1 mg/kg p.o. or i.v. bolus and 1 mg/kg p.o. were administered to the animals, the concentrations of FTY720, and the numbers of lymphocytes, CD20+CD2-B cells, and CD2+CD20-T cells in blood were measured over 23 days. A linear three-compartment model characterized the time course of FTY720 concentrations with a terminal half-life of about 31 h, clearance of about 0.53 l/h/kg, and bioavailability of about 38%. The dynamic responses were not area under the curve (or dose) proportional for either males or females. An indirect response model with a distribution pool captured the cell trafficking data for all doses for each cell type, where initial blood counts (R(0)) were about 7650, 2100, and 5250 cells/microl; maximum fractional inhibition (I(max)) about 0.88, 0.85, and 0.91; influx (k(in)) about 6014, 1312, and 5662 cells/microl/h; efflux (k(out)) about 0.798, 0.555, and 1.08 h(-1); intercompartmental k(cp) about 0.134, 0.192, and 0.082 h(-1); and intercompartmental k(pc) rate constants about 3.9 x 10(-4), and 0.016 and 8.9 x 10(-6) h(-1) for lymphocytes, B cells, and T cells, respectively. The inhibition concentration IC(50) was about 0.48 microg/l for all cells, which was remarkably low. The apparent distribution volumes of peripheral pool (V(p)) were markedly larger than blood volume (V(b)) for all cells. The I(max) for cell trafficking was achieved at doses smaller than that producing graft protection, indicating stronger central than peripheral effects of this drug. The profound cell trafficking effects of FTY720 can be readily captured and interpreted with an extended indirect response model.