REACTIVE RADICAL INTERMEDIATES FORMED FROM ILLUMINATED NIFEDIPINE

Nifedipine, (1,4-dihydro-2,6,dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester) a calcium channel blocker widely used in treatment of hypertension, is strongly photolabile. This may represent a problem in patients taking nifedipine and in handling of nifedipine samples. Reactive radical intermediates were determined and characterized in the process of nifedipine illumination using EPR spectroscopy. On illumination of nifedipine by daylight or by a mercury lamp, a nitroxide radical, R(IL-NIF)(I)NO(.)X was observed (in the first step), in various solvents lie benzene, cyclohexane, methanol, acetonitrile, dimethylsulphoxide, or aqueous suspensions of liposomes. R(IL-NIF)(I) represents the nifedipine skeleton centered with phenyl group, and X is an EPR silent substituent. The generation of R(IL-NIF)(I)NO(.)X is coupled with the formation of nitroso compound, R(IL-NIF)(I)NO, as characterized by W-visible spectroscopy. In a further step, R(IL-NIF)I(N)O abstracts hydrogen from nifedipine skeleton under the formation of R(IL-NIF)(I)NO(.)H radical. In addition to this, in system containing R(IL-NIF)(I)NO and unsaturated lipids, nitroxide radicals R(IL-NIF)(I)NO(.)R(LIPIDS) are formed probably via a pseudo Diels-Alder mechanism (R(LIPIDS) represents lipidic skeleton). The unusually easy photochemical activation of nifedipine is probably stimulated by photosensitization of its nitro group interacting with suitably positioned hydrogen or carboxylic methyl ester group from the pyridinyl ring.