Metabolic fate of¹⁴C-camostat mesylate in man, rat and dog after intravenous administration

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.

Determination of Methyl p-Hydroxy-benzoate, the Metabolite of the Candidate Vaginal Contraceptive Drug 4߰-Carbomethoxyphenyl 4-Guanidinobenzoate Mesylate, in Rabbit Plasma: Application of a rapid and sensitive liquid chromatography-tandem mass spectrometry method

“…4 ¢ -CMGB isv ery instable in plasmaa nd the determination of the parentdrugisimpossible. But the metabolite,P HBA-Me,isv ery stable in plasma.Since4 ¢ -CMGB wasconverted toPHBA-Mecompletelyand quantitatively,the plasmaconcentration of PHBA-Mewasdetermined in thiss tudy.Similarr esults havebeen found in other4 ¢ -guanidinobenzoatecompoundslike nafamostat [12]and camostat [13][14][15].Inan in vivo study,the ester sitewhichconjugatesp-guanidinobenzoica cid and the otherpart wasfound ast he reaction centerasw ell as the sitef orcatabolicc hanges.Afteradministration,the parentdrugwasnotdetected in humano ranimalp lasmaowing torapid hydrolysisof the side-chain ester group,onlyt he metabolitesw eref ound. The metabolismm ayoccur byaid of the esterenzymesw hichd istributed extensivelyin animalblood and tissues.…”

Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity

“…6C). Thus, camostat mesylate is rapidly converted into GBPA under standard cell culture conditions, but the conversion is slower than what is observed in humans (20).…”

“…Expression analyses suggest that they may. TMPRSS13 activated SARS-2-S with similar efficiency as TMPRSS2 and In animal and humans camostat mesylate is rapidly hydrolyzed into the active metabolite 4-(4-guanidinobenzoyloxy) phenylacetic acid (GBPA), which is further hydrolyzed to 4guanidinobenzoic acid (GBA) (18)(19)(20). GBPA was known to retain protease inhibitor activity (34,48) but it was unclear whether GBPA would block TMPRSS2 activity with the same efficiency as camostat mesylate.…”

“…The SARS-CoV-2 isolate hCoV-19/Germany/FI1103201/2020 (GISAID accession EPI-ISL_463008) was isolated at the Institute of Virology, Muenster, Germany, from a patient returning from the Southern Tyrolean ski areas and propagated in Vero-TMPRSS2 cells. Calu-3 cells were pre-incubated for 2 h with 2-fold concentrated camostat mesylate or FOY-251 (2,20 or 200 µM), or DMSO (control), before they were inoculated with SARS-CoV-2 at an MOI of 0.001 or 0.01. For this, the identical volume of virus-containing medium was added to the inhibitor-containing medium on the cells (resulting in 1-fold concentrated camostat mesylate or FOY-251; 1, 10 or 100 µM).…”

TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets

“…Another promising TMPRSS2 inhibitor candidate for COVID-19 treatment is the broad range protease inhibitor camostat. Camostat mesylate is a phenyl-4-guanidinobenzoate derivative originally developed under the name FOY-305 for the treatment of pancreatitis (Tanaka et al, 1979; Midgley et al, 1994) and has been shown to efficiently inhibit replication of different CoV in cell culture and experimentally infected mice (Kawase et al, 2012; Shirato et al, 2013; Zhou et al, 2015). Recently, Hoffmann et al showed that pretreatment of human Caco-2 colon cells and human airway cells with camostat mesylate markedly reduced entry of SARS-CoV-2 as well as VSV pseudotypes containing the SARS-CoV-2 S protein (Hoffmann et al, 2020).…”