Physicochemical methods were used to explore the regularities of complexing between the calcium channel blocker nifedipine (NF) and pharmaceutically acceptable complex-forming glycyrrhizic acid (GA) in view of the discovered influence of GA on the therapeutic activity of NF. 1H NMR (including relaxation measurements) and UV-vis spectra have produced illustrative evidence that NF forms stable complexes with GA within a wide concentration range, from 0.05 to 5 mM. At low GA concentrations, below 0.5 mM, NF forms an inclusion complex where each NF molecule is bound by two molecules of GA. Computer simulations of the NMR experimental data have shown that, in aqueous solution, the stability constant of this complex, K, is about 10(5) M(-1). At higher concentrations, GA forms large micelle-like aggregates which increase the water solubility of NF. Quenching of chemically induced dynamic nuclear polarization effects in the photoinduced interaction of the NF-GA complex with tyrosine suggests that complex formation with GA completely blocks the single electron-transfer step between NF and the amino acid. This, arguably, could explain the increased therapeutic activity of GA complexes, since GA might protect the drug molecule from the reaction with amino acid residues of the receptor binding site.
CIDNP techniques were applied to the investigation of the elementary mechanism of photoinduced interaction between anti-arrhythmic drug lappaconitine and amino acids tyrosine and tryptophan. It has been shown that the reactions involve the formation of lappaconitine radical anion. Lappaconitine radical anion is unstable and rapidly eliminates N-acetyl anthranilic acid via protonation and ether bond cleavage. The rate constant of ether bond cleavage was estimated to be equal to 4 x 10(5) s(-1). The role of single electron transfer is discussed in the light of the model of drug-receptor interactions.
NMR and UV-vis spectroscopy have been used to study the complexation of antiarrhythmic alkaloid lappaconitine with an efficient complexing agent from licorice, glycyrrhizic acid, which is known to profoundly influence the therapeutic activity of the alkaloid in the complex. In MeOH, DMSO, or aqueous solutions, lappaconitine has been shown to form a stable complex with glycyrrhizic acid with 1:1 stoichiometry over a broad concentration range from 1 microM to 300 microM. The stability constant K(11) equals 2.0 x 10(5) M(-1) in aqueous solution. A similar complex of lappaconitine hydrobromide--the pharmaceutical formulation used in the treatment of arrhythmia--is 2 orders of magnitude less stable than pure lappaconitine. A notable decrease in the rate of the photoinduced electron-transfer reaction between lappaconitine in a complex with glycyrrhizic acid and tyrosine allows the suggestion of an explicit interrelation between the suppressed chemical reactivity of the bound alkaloid and the changes of its therapeutic efficiency.
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