Pharmacokinetics and metabolism of intravenous pirfenidone in sheep.

Pirfenidone, a promising antifibrotic agent, was administered intravenously to six female sheep at 30 mg/kg. Four sheep received 14C-pirfenidone simultaneously. Plasma and urine were obtained for assay of pirfenidone and its metabolites over two days, and tissues were obtained via necropsy. Samples were analysed for pirfenidone and metabolites using HPLC-MS and flow scintillation spectrometry. Plasma pirfenidone disappeared with first order kinetics with a clearance of 1.2 l/kg/h, half-life of 24 min, and distribution volume of 0.71 l/kg. After 48 h, the organs containing the largest quantity of 14C were lungs, liver and intestinal wall. Tissues with the highest concentration of 14C were lung, kidney, brain, liver, lymph node and adipose. Metabolites found in plasma and urine were hydroxypirfenidone (half-life of 44 min) and carboxypirfenidone. Additional metabolites found in urine were hydroxypirfenidone glucuronide and acetoxypirfenidone. Approximately, 80% of the tracer eventually appeared in the urine, and approximately 50% of it was in the form of identifiable metabolites. Less than 1% of the dose appeared in the urine in the form of the parent drug. Quantitatively, most of the metabolites appeared in the urine within 2 h. Thus, the drug is rapidly and completely metabolized.