Kinetics of Alpha-Difluoromethylornithine: An Irreversible Inhibitor of Ornithine Decarboxylase

Clin Pharmacol Ther. 1981 Aug;30(2):210-7. doi: 10.1038/clpt.1981.150.

Abstract

We gave alpha-difluoromethylornithine (DFMO), a selective, irreversible inhibitor of ornithine decarboxylase, to six health 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 (t 1/2) for all four doses studied of 199 +/- 6 min (+/- SD). Mean total body clearance (ClT) 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 (aVD) 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 mg/kg orally, and 78% and 81 +/- 8% after 5 and 10 mg/kg 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 leads to infinity). Since doubling of the dose resulted in a doubling of the mean AUC 0 leads to infinity and since other kinetic parameters, such as aVD, t 1/2, ClT, and the urinary recovery of unchanged drug, were essentially the same at all doses, DFMO kinetics follow a dose-linear model.

MeSH terms

  • Administration, Oral
  • Adult
  • Eflornithine
  • Humans
  • Infusions, Parenteral
  • Kinetics
  • Male
  • Models, Biological
  • Ornithine / administration & dosage
  • Ornithine / analogs & derivatives*
  • Ornithine / metabolism
  • Ornithine Decarboxylase Inhibitors

Substances

  • Ornithine Decarboxylase Inhibitors
  • Ornithine
  • Eflornithine