BLOOD DISTRIBUTION AND SINGLE-DOSE PHARMACOKINETICS OF LEFLUNOMIDE

Leflunomide (HWA 486, LEF) is a novel isoxazole derivative with potent immunosuppressive properties. LEF is converted to its active metabolite (A77 1726) after absorption. Presently, the blood distribution and pharmacokinetics of LEF have not been reported. Such information would prove invaluable in determining the appropriate medium for analysis and optimal immunosuppressive dosing regimes. In this study, A77 1726 was found to be primarily associated (> 95%) with the lipoprotein free fraction of plasma at all tested concentrations ranging from 0.4 to 100 mg/L. Detectable levels of A77 1726 (0.34 +/- 0.18 mg/L), analyzed by HPLC, were found in the plasma free fraction only at the highest tested concentration (100 mg/L. Single-dose pharmacokinetics of A77 1726 (i.v.) and HWA 486 (p.o.) were investigated in five healthy New Zealand white rabbits. The half-lives (t(1/2)) of A77 1726 i.v. and HWA 486 p.o. administration were 3.88 +/- 2.3 and 3.18 +/- 1.6 h, respectively. The volume of distribution by both routes of administration indicates minimal distribution into tissues (Vdss(p.o.) = 0.14 +/- 0.03 L/kg and Vdss(i.v.) = 0.09 +/- 0.02 L/kg). The mean residence time of A77 1726 was greater after oral administration of LEF (MRT(p.o.) = 10.54 +/- 2.6 h and MRT(i.v.) = 6.76 +/- 1.0 h). Identical areas under the curve suggest bioavailability was 100% (AUC(p.o.) = 421.16 +/- 204.5 mg . h/L and AUC(i.v.) = 399.75 +/- 126.9 mg . h/L).