Effect of IS01957, a para‐coumaric acid derivative on pharmacokinetic modulation of diclofenac through oral route for augmented efficacy

Abstract

Diclofenac is one of the world's largest selling nonsteroidal anti‐inflammatory drugs. The major concerns related to oral diclofenac therapy are gastrointestinal and cardiovascular side effects for which explicitly emphasis has been given to use it at lowest effective dose for the shortest duration. On the other hand, IS01957 has been designed under the purview of anti‐inflammatory drug and bioavailability enhancer. IS01957 have dual action on inflammation and nociception with acceptable safety profile. In the quest for a suitable combination with improved therapeutic efficacy and better tolerability, pharmacodynamic and pharmacokinetic interaction studies were performed for diclofenac with or without IS01957 in mice model. Results showed that IS01957 enhanced both anti‐inflammatory effect and plasma concentration of diclofenac upon concomitant oral administration. These interesting results steered to enumerate the possible role of IS01957 towards diclofenac pharmacokinetics through a panel of mechanistic investigations: (a) BCRP dependent ATPase activity was markedly interfered by IS01957; (b) IS01957 increased the intestinal permeability of diclofenac in the single pass in‐situ perfusion model; (c) IS01957 inhibited the CYP2C9 catalyzed diclofenac 4‐hydroxylation in human liver microsomes. Immunoblotting results suggest that diclofenac action was improved significantly in the presence of IS01957 involving MAPK pathways. Finally acute gastric damage study showed that IS01957 in combination with diclofenac was better to improve the desired PGE2 level as compare to alone. In nutshell, IS01957 have potential to augment the efficacy of diclofenac through pharmacokinetic modulation. Further investigations are required for dose reduction of diclofenac to combat its liabilities before going into clinical setting.

Description of Druglike Properties of Safranal and Its Chemistry behind Low Oral Exposure

“…This is a colorimetric assay to measure the release of inorganic phosphate in the reaction mixture composed of membrane protein, test compound, and ATP. BCRP-dependent ATPase activity for safranal (1.25–20 μM) was also performed using human BCRP membrane in the same manner as mentioned in the case of P-gp-dependent ATPase activity except cyclosporine (10 μM) was used as standard . The chemical stability of safranal in SGF and SIF was determined by incubating safranal (500 μM) in the respective fluid for 2 and 4 h, respectively .…”

“…Safranal concentration in the sample was determined by HPLC (Table ) using a matrix match calibration curve where standards were prepared by spiking a known amount of safranal into blank plasma. After that, the obtained plasma concentration data at respective time points were analyzed to determine the pharmacokinetic parameters by PK Solutions software (Summit Research Services) using the noncompartmental method. , …”

“…BCRP-dependent ATPase activity for safranal (1.25−20 μM) was also performed using human BCRP membrane in the same manner as mentioned in the case of P-gp-dependent ATPase activity except cyclosporine (10 μM) was used as standard. 35 The chemical stability of safranal in SGF and SIF was determined by incubating safranal (500 μM) in the respective fluid for 2 and 4 h, respectively. 36 The sample spiked with safranal at the same concentration level but without incubation was considered as 0 h. Safranal concentration was determined by HPLC as described in Table 1.…”

Effect of Disease State on the Pharmacokinetics of Bedaquiline in Renal-Impaired and Diabetic Rats

“…Moreover, diabetic patients are prone to renal impairment . In this direction, it is well known that a drop or rise in plasma concentration of the drug may lead to therapeutic failure and growing resistance for antibiotics or enhance dose-dependent adverse effects, respectively. − …”

Formulation, Development and Physicochemical Characterization of Diclofenac Topical Emulgel

“…Our earlier discovery p-coumaric acid derivative was found to be suitable for intraperitoneal as well as oral route of administration with good absorption rate in mice plasma [35]. Later study also proved that there was shown improvement in diclofenac action in the presence of IS01957 involving MAPK pathways when associated oral administration [36]. Hence to demonstrate the important factors behind permeation of drug formulations, in-vitro release studies were under taken across the cellophane membrane using a diffusion cell.…”