Kinetics of α‐difluoromethylornithine: An irreversible inhibitor of ornithine decarboxylase

We gave α‐difluoromethylornithine (DFMO), a selective, irreversible inhibitor of ornithine decarboxylase, to six healthy men in single intravenous doses of 5 and 10 mg/kg body weight and oral doses of 10 and 20 mg/kg. Plasma concentrations were monitored during the 24 hr after each dose. Urine was collected from 0 to 24 hr after drug and amount of unchanged drug excreted was determined. Peak plasma concentrations were reached within 6 hr after oral doses. The decay of the plasma concentrations followed first‐order kinetics with a mean half‐life (t½) for all four doses studied of 199 ± 6 min (±SD). Mean total body clearance (Cl T ) for the four doses was 1.20 ± 0.06 ml · min −1 · kg −1 . Mean renal clearance was determined as 0.99 ± 0.03 ml · min −1 · kg −1 , accounting for 83% of drug elimination. Mean apparent volume of distribution (aV D ) was 0.337 ± 0.031 l/kg −1 , corresponding to 24 l for 70 kg of body weight. The amount of unchanged drug in 24‐hr urine samples was 47 ± 7% and 40 ± 11% after 10 and 20 mglkg orally, and 78% and 81 ± 8% after 5 and 10 mglkg intravenously. Bioavailability of the 10 mg/kg dose was estimated as 58% from the urinary recoveries and as 54% from the areas under the plasma concentration curves (AUC 0→∞ ). Since doubling of the dose resulted in a doubling of the mean AUC 0→∞ and since other kinetic parameters, such as aV D , t½, Cl T , and the urinary recovery of unchanged drug, were essentially the same at all doses, DFMO kinetics follow a dose‐linear model. Clinical Pharmacology and Therapeutics (1981) 30, 210–217; doi: 10.1038/clpt.1981.150