Phototransformations of pitavastatin - The inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase

Abstract

Pitavastatin (PTV) - an important cholesterol-lowering drug, is one of the most potent inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the key enzyme in cholesterol biosynthesis. PTV is sensitive to light, and upon exposure to radiation from the UVA and UVC regions undergoes partial decomposition forming photoproducts. In this study both experimental and theoretical methods were used to get insight into photophysical and photochemical properties of PTV with respect to its primary photochemistry. The PTV photodegradation quantum yield value was determined to be Ф = 0.011 (±0.002). PTV was found to undergo an intersystem crossing, however 3PTV* was formed with a low efficiency due partially to fluorescent properties exhibited by the statin. The lifetime of the excited singlet 1PTV* was calculated to be about 130 (±20) ps. 3PTV* was shown to be not involved in the formation of PTV primary photoproduct. Both PTV and its primary photoproduct were found to be able to generate singlet oxygen. Two different structures of PTV primary photoproduct were assumed to be possible on the basis of experimental measurements and quantum chemical modelling. The study provides mechanistic explanations of the both structures formation. The obtained results address to the lack of data existing till now in the scientific literature with regard to PTV phototransformations, are of great importance for safety of patients who require therapy with the statin, and should be taken into account in studies of the drug’s side effects.