Metabolic fate of 14C-camostat mesylate in man, rat and dog after intravenous administration

Xenobiotica. 1994 Jan;24(1):79-92. doi: 10.3109/00498259409043223.

Abstract

1. The metabolic fate of N,N-dimethylcarbamoylmethyl 4-(4-guanidino[14C]benzoyloxy)phenylacetate methanesulphonate (14C-camostat mesylate) was investigated after i.v. administration to man (12-h infusion), and to rat and dog (bolus injection). 2. Renal excretion (mainly in 24 h) accounted for at least 80% dose in all three species, and the only two important metabolites were identified as 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) and 4-guanidinobenzoic acid (GBA). 3. Parent drug was not detected in human plasma either during or after infusion of 14C-camostat mesylate owing to rapid hydrolysis of the side-chain ester group (t1/2 < 1 min). Steady-state levels of both GBPA and GBA in plasma were apparently attained by the end of the infusion period. Mean terminal half-life, systemic clearance and apparent volume of distribution at steady-state of GBPA in man were 1.0 h, 6.4 ml/min per kg and 0.38 l/kg, respectively, and the corresponding values for GBA were 2.4 h, 4.7 ml/min per kg and 1.01/kg respectively. 4. Radioactivity was rapidly distributed to most tissues after bolus i.v. doses of 14C-camostat mesylate to rats and dogs, with highest levels being associated with the liver and kidney, the two main organs of drug elimination. Concentrations in the pancreas, a possible site for drug action, were generally lower than those in plasma.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Benzoates / blood
  • Benzoates / pharmacokinetics
  • Biotransformation
  • Blood Proteins / metabolism
  • Carbon Radioisotopes
  • Dogs
  • Gabexate* / analogs & derivatives*
  • Guanidines / blood
  • Guanidines / metabolism*
  • Guanidines / pharmacokinetics
  • Humans
  • Infusions, Intravenous
  • Male
  • Protease Inhibitors / blood
  • Protease Inhibitors / metabolism*
  • Protease Inhibitors / pharmacokinetics
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution
  • Trypsin Inhibitors / blood
  • Trypsin Inhibitors / metabolism*
  • Trypsin Inhibitors / pharmacokinetics

Substances

  • Benzoates
  • Blood Proteins
  • Carbon Radioisotopes
  • Guanidines
  • Protease Inhibitors
  • Trypsin Inhibitors
  • camostat
  • 4-guanidinobenzoate
  • Gabexate
  • 4-(4-guanidinobenzoyloxy)phenylacetic acid