Norfloxacin is a fluoroquinolone (FQ) antibiotic that has been reported to cause cutaneous photosensitivity in animals and occasionally in humans. We have studied the fluorescence and singlet oxygen (1O2)-generating properties of norfloxacin. Upon UV excitation the drug fluoresces in water, and the relative intensities of two major fluorescence bands at ca 420 and 450 nm are affected by pH. The overall quantum yield of fluorescence (phi F) is also strongly pH dependent: phi F is low in 0.2 N HCl solution (0.2), increasing steeply to 0.12 at pH 4, then gradually decreasing to 0.01 at pH 10. The changes in phi F are accompanied by changes in fluorescence lifetime from 0.6 ns at pH 1 to 1.8 ns at pH 4. Norfloxacin exhibits phosphorescence in low temperature glasses. The formation of a triplet state at room temperature is also suggested by 1O2 phosphorescence in aerobic D2O. This phosphorescence is "self-quenched" by norfloxacin itself with an efficiency that is pH dependent: kq is 7.9 x 10(6) M-1 s-1 at pD 4, decreases to 1.9 x 10(6) M-1 s-1 at pD 7.5 but then increases about 20-fold in alkaline D2O solutions. This quenching causes the observed 1O2 production by norfloxacin (0.1 mM) to show a maximum at around pH 8-9. However, after correction for self-quenching, the quantum yield of 1O2 production (phi 50)y measured by using perinaphthenone as a standard, yielded the following values: phi s0 is about 0.07 in 0.2 N DCI solution, 0.08 at pH 7.5 and then increases smoothly to approximately 0.2 in 0.1 M NaOD solution. The relatively high, unquenched 1O2 production at physiological pH 7.4 (phi s0 approximately 0.08) suggests that 1O2 reactions may play an important role in the cutaneous phototoxicity of norfloxacin and other FQ antibiotics.
The azide ion is a strong physical quencher of singlet molecular oxygen (1O2) and is frequently employed to show involvement of 1O2 in oxidation processes. Rate constants (k(q)) for the quenching of 1O2 by azide are routinely used as standards to calculate k(q) values for quenching by other substrates. We have measured k(q) for azide in solvent mixtures containing deuterium oxide (D2O), acetonitrile (MeCN), 1,4-dioxane, ethanol (EtOH), propylene carbonate (PC), or ethylene carbonate (EC), mixtures commonly used for many experimental studies. The rate constants were calculated directly from 1O2 phosphorescence lifetimes observed after laser pulse excitation of rose bengal (RB), used to generate 1O2. In aqueous mixtures with MeCN and carbonates, the rate constant increased nonlinearly with increasing volume of organic solvent in the mixtures. k(q) was 4.78 x 10(8) M(-1) s(-1) in D2O and increased to 26.7 x 10(8) and 27.7 x 10(8) M(-1) s(-1) in 96% MeCN and 97.7% EC/PC, respectively. However, in EtOH/D2O mixtures, k(q) decreased with increasing alcohol concentration. This shows that a higher solvent polarity increases the quenching efficiency, which is unexpectedly decreased by the proticity of aqueous and alcohol solvent mixtures. The rate constant values increased with increasing temperature, yielding a quenching activation energy of 11.3 kJ mol(-1) in D2O. Our results show that rate constants in most solvent mixtures cannot be derived reliably from k(q) values measured in pure solvents by using a simple additivity rule. We have measured the rate constants with high accuracy, and they may serve as a reliable reference to calculate unknown k(q) values.
The azide ion is a strong physical quencher of singlet molecular oxygen (1O2) and is frequently employed to show involvement of 1O2 in oxidation processes. Rate constants (kq) for the quenching of 1O2 by azide are routinely used as standards to calculate kq values for quenching by other substrates. We have measured kq for azide in solvent mixtures containing deuterium oxide (D2O), acetonitrile (MeCN), 1,4‐dioxane, ethanol (EtOH), propylene carbonate (PC), or ethylene carbonate (EC), mixtures commonly used for many experimental studies. The rate constants were calculated directly from 1O2 phosphorescence lifetimes observed after laser pulse excitation of rose bengal (RB), used to generate 1O2. In aqueous mixtures with MeCN and carbonates, the rate constant increased nonlinearly with increasing volume of organic solvent in the mixtures. kq was 4.78 × 108M−1 s−1 in D2O and increased to 26.7 × 108 and 27.7 × 108M−1 s−1 in 96% MeCN and 97.7% EC/PC, respectively. However, in EtOH/D2O mixtures, kq decreased with increasing alcohol concentration. This shows that a higher solvent polarity increases the quenching efficiency, which is unexpectedly decreased by the proticity of aqueous and alcohol solvent mixtures. The rate constant values increased with increasing temperature, yielding a quenching activation energy of 11.3 kJ mol−1 in D2O. Our results show that rate constants in most solvent mixtures cannot be derived reliably from kq values measured in pure solvents by using a simple additivity rule. We have measured the rate constants with high accuracy, and they may serve as a reliable reference to calculate unknown kq values.
The fluoroquinolone antibacterial norfloxacin (NF) is a moderate photosensitizer of singlet molecular oxygen (1O2). We have studied photosensitization by NF as a function of medium polarity and proticity in solvent mixtures. We have used 1,4-dioxane and propylene carbonate mixtures to keep proticity constant while modulating polarity, and water/D2O and ethylene carbonate mixtures to alter proticity without large changes in polarity. The absorption spectrum of NF was little affected by solvent changes, as compared to the fluorescence spectrum that exhibited as much as a 50 nm blue-shift, e.g. 1,4-dioxane versus D2O. The quantum yield of NF fluorescence saturated at an almost 10 times higher value (approximately 0.14) when proticity was increased by added water, up to 0.2 mol fraction, to ethylene carbonate. Less pronounced, the increasing polarity in 1,4-dioxane/propylene carbonate mixtures affected the fluorescence yield much less. Norfloxacin produces 1O2 and is able to quench 1O2. The rate constant for 1O2 quenching is 4.5 x 10(7) M-1 s-1 in propylene carbonate but decreases ca four times in D2O. The quantum yield of 1O2 photogeneration was also up to five times higher in solvents that were both protic and polar than vice versa. Our data show that NF is more photochemically active in an environment that is both protic and polar. This suggests the involvement of polar excited state(s) and possible proton/hydrogen transfer during photoexcitation. Similar processes may initiate the phototoxic response reported in some patients treated with the fluoroquinolone drugs. The phototoxicity of NF and other fluoroquinolone antibiotics may strongly depend on their localization in hydrophilic or hydrophobic cell/tissue regions.
The fluoroquinolone antibacterial norfloxacin (NF) is a moderate photosensitizer of singlet molecular oxygen (1O2). We have studied photosensitization by NF as a function of medium polarity and proticity in solvent mixtures. We have used 1,4-dioxane and propylene carbonate mixtures to keep proticity constant while modulating polarity, and water/D2O and ethylene carbonate mixtures to alter proticity without large changes in polarity. The absorption spectrum of NF was little affected by solvent changes, as compared to the fluorescence spectrum that exhibited as much as a 50 nm blue-shift, e.g. 1,4-dioxane versus D2O. The quantum yield of NF fluorescence saturated at an almost 10 times higher value (approximately 0.14) when proticity was increased by added water, up to 0.2 mol fraction, to ethylene carbonate. Less pronounced, the increasing polarity in 1,4-dioxane/propylene carbonate mixtures affected the fluorescence yield much less. Norfloxacin produces 1O2 and is able to quench 1O2. The rate constant for 1O2 quenching is 4.5 x 10(7) M-1 s-1 in propylene carbonate but decreases ca four times in D2O. The quantum yield of 1O2 photogeneration was also up to five times higher in solvents that were both protic and polar than vice versa. Our data show that NF is more photochemically active in an environment that is both protic and polar. This suggests the involvement of polar excited state(s) and possible proton/hydrogen transfer during photoexcitation. Similar processes may initiate the phototoxic response reported in some patients treated with the fluoroquinolone drugs. The phototoxicity of NF and other fluoroquinolone antibiotics may strongly depend on their localization in hydrophilic or hydrophobic cell/tissue regions.
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