In vitro biodistribution studies on clinically approved FGFR inhibitors ponatinib, nintedanib, erlotinib and an investigational inhibitor KP2692

Eur J Pharm Sci. 2023 Nov 25:106651. doi: 10.1016/j.ejps.2023.106651. Online ahead of print.ABSTRACTBinding towards human serum albumin (HSA) and α1-acid glycoprotein (AGP) of three approved fibroblast growth factor receptor (FGFR) inhibitors ponatinib (PON), nintedanib (NIN) and erdafitinib (ERD), as well as the experimental drug KP2692 was studied by means of spectrofluorometric and UV-visible spectrophotometric methods. Additionally, proton dissociation processes, lipophilicity, and fluorescence properties of these four molecules were investigated in detail. The FGFR inhibitors were predominantly presented in their single protonated form (HL+) at pH 7.4 (at blood pH). At gastric pH (pH 1-2) the protonated forms (+1 - +3) are present, which provide relatively good aqueous solubility of the drugs. All of the four inhibitors are highly or extremely lipophilic at pH 7.4 (logD7.4≥2.7). At acidic pH 2.0 PON and ERD are rather lipophilic, NIN is amphiphilic, while KP2692 is highly hydrophilic. All four compounds bind to HSA and AGP. Moderate binding of PON, KP2692 and NIN was found towards albumin (logK' = 4.5-4.7), while their affinity for AGP was about one order of magnitude higher (logK' = 5.2-5.7). ERD shows a larger affinity for both proteins (logK'HSA ≈ 5.2, logK'AGP ≈ 7.0). The computed constants were used to model the distribution of the FGFR inhibitors in blood plasma under physiological and pathological (acute phase) conditions. The changing levels of the two pro...
Source: European Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Authors: Source Type: research