Metabolic fate of 14C-camostat mesylate in man, rat and dog after intravenous administration.
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.
Midgley
I
I
Huntingdon Research Centre Ltd., UK.
Hood
A J
AJ
Proctor
P
P
Chasseaud
L F
LF
Irons
S R
SR
Cheng
K N
KN
Brindley
C J
CJ
Bonn
R
R
D000328:Adult; D000818:Animals; D001565:Benzoates / Q000097:blood / Q000493:pharmacokinetics; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D004285:Dogs; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives*; D006146:Guanidines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011480:Protease Inhibitors / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014361:Trypsin Inhibitors / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics
D001565:Benzoates; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D004952:Esters; D006146:Guanidines; D011480:Protease Inhibitors; D014361:Trypsin Inhibitors; C034532:camostat; C023856:4-guanidinobenzoate; D016670:Gabexate; C045130:4-(4-guanidinobenzoyloxy)phenylacetic acid