01908nas a2200205   4500000000100000008004100001100001500042700001300057700001600070700001500086700001200101700001000113700001700123700001300140700001500153700001500168245007200183520143300255022001401688       2017                            d1 aMurashov M1 aLaLone V1 aRzeczycki P1 aKeswani RK1 aYoon GS1 aSud S1 aRajeswaran W1 aLarsen S1 aStringer K1 aRosania GR00aThe Physicochemical Basis of Clofazimine-Induced Skin Pigmentation.3 a<p>Clofazimine is a weakly basic, FDA-approved antibiotic recommended by the World Health Organization to treat leprosy and multi-drug-resistant tuberculosis. Upon prolonged treatment, clofazimine extensively bioaccumulates and precipitates throughout the organism, forming crystal-like drug inclusions (CLDIs). Because of the drug's red color, it is widely believed that clofazimine bioaccumulation results in skin pigmentation, its most common side effect. To test whether clofazimine-induced skin pigmentation is due to CLDI formation, we synthesized a closely related clofazimine analog that does not precipitate under physiological pH and chloride conditions that are required for CLDI formation. Despite the absence of detectable CLDIs in mice, administration of this analog still led to significant skin pigmentation. In clofazimine treated mice, skin cryosections revealed no evidence of CLDIs when analyzed with a microscopic imaging system specifically designed for detecting clofazimine aggregates. Rather, the reflectance spectra of the skin revealed a signal corresponding to the soluble, free base form of the drug. Consistent with the low concentrations of clofazimine in the skin, these results suggest that clofazimine-induced skin pigmentation is not due to clofazimine precipitation and CLDI formation, but rather to the partitioning of the circulating, free base form of the drug into subcutaneous fat.</p>
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