Theoretical Study of Ibuprofen Phototoxicity

Abstract

The photochemical properties and degradation of the common nonsteroid anti-inflammatory drug ibuprofen is studied by means of hybrid density functional theory. Computed energies and properties of various species show that the deprotonated form dominates at physiological pH, and that the species will not be able to decarboxylate from a singlet excited state. Instead, decarboxylation will occur, with very high efficiency, provided the deprotonated compound can undergo intersystem crossing from an excited singlet to its excited triplet state. In the triplet state, the C-C bond connecting the carboxyl group is elongated, and the CO2 moiety detaches with a free energy barrier of less than 0.5 kcal/mol. Depending on the local environment, the decarboxylated product can then either be quenched through intersystem crossing (involving the possible formation of singlet oxygen) and protonation, or serve as an efficient source for superoxide anions and the formation of a peroxyl radical that will initiate lipid peroxidation.

Farmakoekologija – okolišna sudbina lijekova

“…Kvantnokemijski modeli standardna su procedura u tumačenju mehanizama organskih reakcija, no rijetki su primjeri kvantnokemijskih studija u kojima su strukture lijekova objekt istraživanja. U posljednjih deset godina objavljeno je tek nekoliko studija koje prikazuju uspješnu primjenu kvantnokemijskih metoda u rasvjetljavanju kemijske sudbine lijekova u okolišu: etinilestradiol, 38,39 diklofenak, 40 ibuprofen, 41 naproksen, 42 klorambucil, 43 te acetaminofen. 44 U nabrojanim studijama prikazani su uglavnom hidrolitički i fotokemijski inducirani procesi pregrađivanja.…”

New nonsteroidal anti‐inflammatory molecules with reduced photodegradation side effects and enhanced COX‐2 selectivity

“…Previous studies exploring the photodegradation mechanisms of KP, IBU, and NP [39][40][41] served as basis for the modifications displayed in Figure 1(B). The geometries of the modified molecules (1MKP, 2MKP, 1MIBU, 2MIBU, 1MNP, and 2MNP), in their neutral and deprotonated anionic (acidic) forms, were optimized using the same level of theory as used to study the parent drugs, i.e., B3LYP/6-31G (d,p) [45,46].…”

“…Phototoxic degradation mechanisms of the most commonly used drugs (due to their availability as OTC agents, dispensed in large quantities with or without prescription) ketoprofen (KP), ibuprofen (IBU), naproxen (NP), flurbiprofen (FBP), diclofenac (DF), suprofen (SUP), and tiaprofenic acid (TP) have been extensively studied experimentally and are well documented, e.g., [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Recently, studies have been performed using computational quantum chemistry techniques (DFT, TD-DFT) to investigate the detailed photodegradation mechanisms of these compounds [39][40][41][42][43][44]. Despite the fact that such a large number of experimental studies have been performed to date; however, to our knowledge, no new or modified drugs have been proposed or dispensed into the market that are considered to reduce or prevent the phototoxicity of this NSAID family.…”

“…[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]) and our previous theoretical quantum chemical studies [39][40][41][42][43][44], new compounds are herein reported, obtained by modifying the parent NSAIDs with the aim to be more photostable. To investigate their activity and selectivity toward the COX isoforms, molecular modeling studies are also carried out with the help of information available from X-ray diffraction studies.…”

“…The photochemical reactions forming all these species can be experimentally investigated by spectroscopic techniques, of which laser flash photolysis and UV-visible spectrophotometry are particularly common. In this context, KP [39] spontaneously decarboxylates from its deprotonated triplet state (without energy barrier), whereas the corresponding deprotonated (acidic) IBU and NP decarboxylate by passing low-energy barrier of <0.3 and 1 kcal/mol, respectively [40,41]. These low barriers of decarboxylation have been raised through the currently introduced modifications, leading to reduced photodegradation potential and hence safer compounds than the parent drug molecules as discussed below.…”