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

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Abstract
.alpha.-Difluoromethylornithine (DFMO), a selective, irreversible inhibitor of ornithine decarboxylase was given to 6 healthy men in single i.v. doses of 5 and 10 mg/kg body wt and oral doses of 10 and 20 mg/kg. Plasma concentrations were monitored during the 24 h after each dose. Urine was collected from 0-24 h after drug and amount of unchanged drug excreted was determined. Peak plasma concentrations were reached within 6 h after oral doses. The decay of the plasma concentrations followed 1st-order kinetics with a mean half-life (t1/2) for all 4 doses studied of 199 .+-. 6 min (.+-. SD). Mean total body clearance (ClT) for the 4 doses was 1.20 .+-. 0.06 ml/min per kg. Mean renal clearance was determined as 0.99 .+-. 0.03 ml/min per kg, accounting for 83% of drug elimination. Mean apparent volume of distribution (.alpha.VD) was 0.337 .+-. 0.031 1/kg , corresponding to 24 l for 70 kg of body wt. The amount of unchanged drug in 24 h urine samples was 47 .+-. 7% and and 40 .+-. 11% after 10 and 20 mg/kg orally, and 78% and 81 .+-. 8% after 5 and 10 mg/kg i.v. 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 (AUC0 .fwdarw..infin.). As doubling of the dose caused a doubling of the mean AUC0 .fwdarw..infin. and as other kinetic parameters, i.e., .alpha.VD, t1/2, Cl and the urinary recovery of unchanged drug, were essentially the same at all doses, DFMO kinetics follow a dose-linear model.