B. Pharmacokinetics in Humans: The pharmacokinetics of leflunomide, based upon plasma concentrations of the active metabolite, have been studied in healthy subjects and in patients with RA.
Following oral administration, leflunomide is rapidly converted to the active metabolite (A77 1726). Animal studies suggest that conversion takes place during passage through both the gut wall and the liver. After oral administration of a 100 mg dose of 14C-leflunomide to healthy volunteers, leflunomide was not detectable in plasma over the plasma sampling period (0.5 hr. to 37 days). Plasma concentrations of total radioactivity and the active metabolite were superimposable, demonstrating extensive conversion to the active metabolite during the absorption process. The minor metabolite, 4-trifluoromethylaniline (TFMA) has been detected in the plasma of animals and man, but at concentrations (ng/ml) much less than those of the active metabolite (g/ml). Urinary and fecal recovery of 14C over 28 days accounted for 43% and 48% of total radioactivity, respectively. The slow but nearly complete recovery of radioactivity as metabolites indicated nearly complete absorption of leflunomide in man. Unchanged leflunomide was not detected in urine or feces. The urinary metabolites were primarily glucuronide conjugates of leflunomide and an oxanilic acid derivative of the active metabolite, while the active metabolite was the primary metabolite in the feces. The metabolic biotransformation of the active metabolite is not controlled by a single enzyme and has been shown to occur in microsomal and cytosolic cellular fractions. The active metabolite is cleared by slow excretion in feces, probably by biliary elimination, and slow metabolism to the oxanilic acid metabolite excreted in urine. After independent intravenous administration of the active metabolite, clearance averaged 31 ml/hr, steady-state volume of distribution of 11L, and elimination half-life of 10 days. A similar clearance estimate (29 17 ml/hr) was obtained from