AbstractsBiology & Animal Science

Distribution of melanin binding drugs – A kinetic study with pigmented and albino rats using SPECT/CT imaging method

by Satu Nurmi

Institution: University of Helsinki
Year: 2015
Keywords: melanin distribution; melanin binding; SPECT/CT; melaniinin jakautuminen; melaniinisitoutuminen; Biofarmasia
Record ID: 1135898
Full text PDF: http://hdl.handle.net/10138/153096


Many drugs are known to bind to melanin, a complex pigment polymer found in several human tissues. Melanin can act as a natural depot by prolonging the effect of the drug and reducing its toxicity. Since it is highly concentrated in the posterior part of the eye, pigment targeted long-acting drug delivery systems are proposed as an option in ocular diseases. In systemic drug delivery, pigment targeted drugs can potentially distribute to any melanin containing tissue. Therefore, the literature review of the thesis concentrates on the characteristics of melanin and melanosomes, drug binding property and melanin distribution in humans and other species. The main objective of the exploratory part was to determine if melanin binding can be studied with SPECT/CT (single photon emission computed tomography / computed tomography) imaging method. Two different melanin binding drugs, chloroquine and nadolol, were selected and labeled with iodine and radioactive iodine (123I). Equilibrium melanin binding of iodinated and non-iodinated drugs was studied in vitro in order to find out if iodination affects to the binding. Melanin binding was studied in vitro also with non-binding reference salicylic acid, I2-salicylic acid and salbutamol. Finally, melanin binding of 123I-choloroquine and 123I-nadolol was studied with SPECT/CT (NanoSPECT/CT, Bioscan Inc., USA) by comparing distribution kinetics between pigmented and albino rat. Drugs were administered intravenously to the tail vena and the distribution was followed in several time points, up to 24 h. Based on in vitro study, iodination increases melanin binding of hydrophilic drugs, nadolol and salicylic acid, significantly. In vivo study showed clear accumulation of 123I-chloroquine in the posterior eye of pigmented rats whereas it was absent from albino rat. Interestingly, 123I-nadolol accumulated in to the nasal cavity of pigmented rats. Aromatic iodination changes electronegative properties of compounds and raises their logP (octanol/water partition coefficient) value affecting to the melanin binding positively. Therefore the effect of the radiotracer to the physicochemical properties of the compound and melanin binding should be determined in vitro. This study showed that SPECT/CT imaging method can be used to study melanin binding in vivo. Because the method is semi-quantitative, also a quantitative method should be incorporated to the study in order to have more powerful data. Additional studies are required for statistical analysis. Useat lääkeaineet sitoutuvat melaniiniin, kemialliselta rakenteeltaan monimutkaiseen pigmenttiin, jota löytyy ihmisen monista kudoksista. Melaniini voi toimia luonnollisena varastona lääkeaineille pidentäen niiden vaikutusaikaa ja vähentäen toksisuutta. Koska sitä löytyy erityisesti silmän takaosasta, jonne lääkeaineiden vieminen on hyvin haastavaa, pigmenttiin kohdennettua lääkemuotoa on esitetty silmälääketieteen uudeksi vaihtoehdoksi. Mikäli pigmenttiin kohdennettu lääke annetaan systeemisesti, on mahdollista, että se jakautuu myös…