Study of Association of 12-Monoketocholic Acid by 1H NMR Relaxation Method

Mihály Pósa,1 Valéria Guzsvány,2 János Csanádi,2,* Júlia Borbás2 and Ferenc Gaál2

1 Laboratory of Physical Pharmacy, Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Republic of Serbia,
2 Department of Chemistry, Faculty of Sciences, University of Novi Sad, Trg Dositeja, Obradovića 3, 21000 Novi Sad, Republic of Serbia
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12-Monoketocholic acid (12-MKC) shows a promotive effect in the transport of some drugs (lidocaine, morphine, quinine, gliclazide, etc.). In the mechanism of pharmacological action of 12-MKC an important role plays its aggregation (self-association), as well as formation of mixed micelles. These phenomena were studied by the 1H NMR spin-lattice relaxation method using solutions of sodium salt of 12-MKC in D2O and in D2O solution saturated with 1-octanol. The function describing the dependence of the spin-lattice relaxation time (T1) on the concentration of Na-12-MKC (cBA) in D2O has one inflexion point (at the concentration of 48 mM), whereas the same function for the saturated solution of 1- octanol has two inflexion points (one at the concentration of 45 mM and the other at 87 mM). These differences in the curves T1 = f(cBA), as well as the shift of the solubilization curve of lecithin in the presence of 1-octanol towards higher concentrations of Na-12-MKC, indicate that sodium salt of this keto-bile acid forms mixed micelles with 1-ocatnol, so that the application of the micellar solution of Na-12-MKC in the presence of 1-octanol decreases membrane toxicity (membrane lysis) of this bile acid. The curves T1 = f(cBA) for methyl esters of 12-MKC and cholic acid in the CDCl3 solution have one inflexion point at the concentration above 5 mM, indicating formation of the micelles of Small’s type, whereas methyl ester of 3,7,12-triketocholic acid forms a gel-like structure.

Keywords: 12-monoketocholic acid, 1H NMR relaxation method, aggregation