Revisiting and Updating the Interaction between Human Serum Albumin and the Non-Steroidal Anti-Inflammatory Drugs Ketoprofen and Ketorolac.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Ketoprofen*/chemistry ; Ketoprofen*/metabolism ; Ketoprofen*/pharmacokinetics ; Anti-Inflammatory Agents, Non-Steroidal*/chemistry ; Anti-Inflammatory Agents, Non-Steroidal*/metabolism ; Anti-Inflammatory Agents, Non-Steroidal*/pharmacokinetics ; Protein Binding* ; Ketorolac*/chemistry ; Ketorolac*/metabolism ; Ketorolac*/pharmacokinetics ; Serum Albumin, Human*/chemistry ; Serum Albumin, Human*/metabolism; Humans ; Circular Dichroism ; Thermodynamics ; Spectrometry, Fluorescence ; Binding Sites

Ketoprofen (KTF) and ketorolac (KTL) are among the most primarily used non-steroidal anti-inflammatory drugs (NSAIDs) in humans to alleviate moderate pain and to treat inflammation. Their binding affinity with albumin (the main globular protein responsible for the biodistribution of drugs in the bloodstream) was previously determined by spectroscopy without considering some conventional pitfalls. Thus, the present work updates the biophysical characterization of the interactions of HSA:KTF and HSA:KTL by ¹ H saturation-transfer difference nuclear magnetic resonance ( ¹ H STD-NMR), ultraviolet (UV) absorption, circular dichroism (CD), steady-state, and time-resolved fluorescence spectroscopies combined with in silico calculations. The binding of HSA:NSAIDs is spontaneous, endothermic, and entropically driven, leading to a conformational rearrangement of HSA with a slight decrease in the α-helix content (7.1% to 7.6%). The predominance of the static quenching mechanism (ground-state association) was identified. Thus, both Stern-Volmer quenching constant ( K SV ) and binding constant ( K b ) values enabled the determination of the binding affinity. In this sense, the K SV and K b values were found in the order of 10 ⁴ M ^-1 at human body temperature, indicating moderate binding affinity with differences in the range of 0.7- and 3.4-fold between KTF and KTL, which agree with the previously reported experimental pharmacokinetic profile. According to ¹ H STD-NMR data combined with in silico calculations, the aromatic groups in relation to the aliphatic moiety of the drugs interact preferentially with HSA into subdomain IIIA (site II) and are stabilized by interactions via hydrogen bonding and hydrophobic forces. In general, the data obtained in this study have been revised and updated in comparison to those previously reported by other authors who did not account for inner filter corrections, spectral backgrounds, or the identification of the primary mathematical approach for determining the binding affinity of HSA:KTF and HSA:KTL.

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UIDB/00313/2020, UIDP/00313/2020, 2020.07504.BD Fundação para a Ciência e Tecnologia

Keywords: biophysical characterization; in silico calculations; non-steroidal anti-inflammatory drugs; pharmacokinetics; spectroscopy

90Y4QC304K (Ketoprofen)
0 (Anti-Inflammatory Agents, Non-Steroidal)
YZI5105V0L (Ketorolac)
ZIF514RVZR (Serum Albumin, Human)

Date Created: 20240713 Date Completed: 20240713 Latest Revision: 20240809

20250114

PMC11243439

10.3390/molecules29133001

38998953