Pharmacokinetics of Nafamostat, a Potent Serine Protease Inhibitor, by a Novel LC-MS/MS Analysis

Oh, Hyeon Seok; Kim, Tae-Hyung; Gu, Dong-Hyeon; Lee, Tae Suk; Kim, So Yeon; Shin, So Young; Shin, Beom Soo

doi:10.3390/molecules27061881

Cited by 4 publications

(1 citation statement)

References 40 publications

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“…Numerous studies have been conducted on various indications using nafamostat. However, animal and clinical studies are limited, likely owing to the instability and polarity of nafamostat [ 12 13 ]. Notably, the reported half-life of nafamostat in plasma is up to 8 min, indicating that nafamostat is rapidly metabolized in the plasma.…”

Section: Introductionmentioning

confidence: 99%

Predicting the systemic exposure and lung concentration of nafamostat using physiologically-based pharmacokinetic modeling

Jeong

Chae

Shin

2022

Transl Clin Pharmacol

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Nafamostat has been actively studied for its neuroprotective activity and effect on various indications, such as coronavirus disease 2019 (COVID-19). Nafamostat has low water solubility at a specific pH and is rapidly metabolized in the blood. Therefore, it is administered only intravenously, and its distribution is not well known. The main purposes of this study are to predict and evaluate the pharmacokinetic (PK) profiles of nafamostat in a virtual healthy population under various dosing regimens. The most important parameters were assessed using a physiologically based pharmacokinetic (PBPK) approach and global sensitivity analysis with the Sobol sensitivity analysis. A PBPK model was constructed using the SimCYP ® simulator. Data regarding the in vitro metabolism and clinical studies were extracted from the literature to assess the predicted results. The model was verified using the arithmetic mean maximum concentration (C max ), the area under the curve from 0 to the last time point (AUC 0-t ), and AUC from 0 to infinity (AUC 0-∞ ) ratio (predicted/observed), which were included in the 2-fold range. The simulation results suggested that the 2 dosing regimens for the treatment of COVID-19 used in the case reports could maintain the proposed effective concentration for inhibiting severe acute respiratory syndrome coronavirus 2 entry into the plasma and lung tissue. Global sensitivity analysis indicated that hematocrit, plasma half-life, and microsomal protein levels significantly influenced the systematic exposure prediction of nafamostat. Therefore, the PBPK modeling approach is valuable in predicting the PK profile and designing an appropriate dosage regimen.

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Section: Introductionmentioning

confidence: 99%

Predicting the systemic exposure and lung concentration of nafamostat using physiologically-based pharmacokinetic modeling

Jeong

Chae

Shin

2022

Transl Clin Pharmacol

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DON/DRP‐104 as potent serine protease inhibitors implicated in SARS‐CoV‐2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach

Oduro‐Kwateng,

Soliman

2024

J of Cellular Biochemistry

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Human transmembrane serine protease 2 (TMPRSS2) is an important member of the type 2 transmembrane serine protease (TTSP) family with significant therapeutic markings. The search for potent TMPRSS2 inhibitors against severe acute respiratory syndrome coronavirus 2 infection with favorable tissue specificity and off‐site toxicity profiles remains limited. Therefore, probing the anti‐TMPRSS2 potential of enhanced drug delivery systems, such as nanotechnology and prodrug systems, has become compelling. We report the first in silico study of TMPRSS2 against a prodrug, [isopropyl(S)‐2‐((S)‐2‐acetamido‐3‐(1H‐indol‐3‐yl)‐propanamido)‐6‐diazo‐5‐oxo‐hexanoate] also known as DRP‐104 synthesized from 6‐Diazo‐5‐oxo‐l‐norleucine (DON). We performed comparative studies on DON and DRP‐104 against a clinically potent TMPRSS2 inhibitor, nafamostat, and a standard serine protease inhibitor, 4‐(2‐Aminoethyl) benzenesulfonyl fluoride (AEBSF) against TMPRSS2 and found improved TMPRSS2 inhibition through synergistic binding of the S1/S1' subdomains. Both DON and DRP‐104 had better thermodynamic profiles than AEBSF and nafamostat. DON was found to confer structural stability with strong positive correlated inter‐residue motions, whereas DRP‐104 was found to confer kinetic stability with restricted residue displacements and reduced loop flexibility. Interestingly, the Scavenger Receptor Cysteine‐Rich (SRCR) domain of TMPRSS2 may be involved in its inhibition mechanics. Two previously unidentified loops, designated X (270−275) and Y (293−296) underwent minimal and major structural transitions, respectively. In addition, residues 273−277 consistently transitioned to a turn conformation in all ligated systems, whereas unique transitions were identified for other transitioning residue groups in each TMPRSS2‐inhibitor complex. Intriguingly, while both DON and DRP‐104 showed similar loop transition patterns, DRP‐104 preserved loop structural integrity. As evident from our systematic comparative study using experimentally/clinically validated inhibitors, DRP‐104 may serve as a potent and novel TMPRSS2 inhibitor and warrants further clinical investigation.

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Drug repurposing for the treatment of COVID-19: Targeting nafamostat to the lungs by a liposomal delivery system

Reus,

Guthmann,

Uhlig

et al. 2023

Journal of Controlled Release

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Pharmacokinetics of Nafamostat, a Potent Serine Protease Inhibitor, by a Novel LC-MS/MS Analysis

Cited by 4 publications

References 40 publications

Predicting the systemic exposure and lung concentration of nafamostat using physiologically-based pharmacokinetic modeling

Predicting the systemic exposure and lung concentration of nafamostat using physiologically-based pharmacokinetic modeling

DON/DRP‐104 as potent serine protease inhibitors implicated in SARS‐CoV‐2 infection: Comparative binding modes with human TMPRSS2 and novel therapeutic approach

Drug repurposing for the treatment of COVID-19: Targeting nafamostat to the lungs by a liposomal delivery system

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