engleski

Determination of lipophilicity of immunosuppressants and folic acid: traditional vs modern approach?

Immunosuppressants azathioprine (AZA), 6- mercaptopurine (6-MP) and 6-thioguanine (6-TG) are one of the most common therapy choices for patients with inflammatory bowel disease (IBD). Malabsorption of many nutrients, including folic acid (FA), a vitamin whose inadequate intake is associated with megaloblastic anemia and possible increase of colorectal cancer risk, is often presented in these patients. So as to improve the adherence of patients, a fixed dose combination of one of the immunosuppressants and FA is proposed. The aim of this work was to determine the lipophilicity of the drugs in order to evaluate their pharmacokinetic properties, as well as potentially simplify the formulation process. LogD values were determined by traditional shake-flask procedure followed by HPLC measurements of aqueous phase (phosphate buffer pH 7.4) before and after equilibration with n- octanol. Furthermore, two sophisticated indirect approaches were used. TLC measurements were done using RP-C18 F254 silicagel plates, while HPLC measurements were done using various stationary phases octadecylsilyl, immobilized artificial membrane, human serum albumin and α-1 acid glycoprotein. Finally, in silico approximations of logP, logD and plasma protein binding were predicted by 14 on-line based platforms. Experimental results showed the highest lipophilicity for AZA (logD = 0.08), while 6-TG (logD = -0.29) and 6-MP (logD = -0.29) were slightly less lipophilic. FA varied from the most hydrophilic of the analytes to moderately lipophilic, depending on the method used. Significant correlations (R2 from 0.869 to 0.973) have been obtained between predicted and experimental values ; on-line platforms which showed the most prominent correlations were PreADMET, pkCSM, Chemicalize, ALOGPS, ADMETLab and Mcule. In this work various parameters describing pharmacokinetic properties have been determined experimentally and obtained data were correlated with values predicted by on-line platforms. Correlations obtained between these values imply that such platforms could potentially be used in screening of similar molecules in terms of physicochemical and pharmacokinetic properties, thus enhancing drug discovery and drug development effectiveness. This work has been supported in part by the Croatian Science Foundation under the project number [UIP-2017- 05-3949]. This work has been supported in part by the European Union from the European Social Fund.

IBD, ADME, HPLC

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