Preliminary Evaluation About Druggability On Four Novel Modifiers Of 18β-glycyrrhetinic Acid And Oleanolic Acid

Glycyrrhetinic acid and oleanolic acid are made use of widely in protecting hepatitis. But they have the shortcoming in first pass effect and short of half-life. In the prior study the compounds of cis-3-O-[4-(R)-(3-Chlorophenyl)-2-oxo-1,3,2-diox-aphorinan-2-yl]-18β-glycyrrhetinic acid and cis-3-O-[4-(S)-(3-Chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-18β-glycyrrhetinic acid, cis-3-O-[4-(R)-(3-Chlorophe-nyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl] and cis-3-O-[4-(S)-(3-Chlorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]-oleanolic acid were synthesized by prof. Jiang Tao team of Key Laboratory of Marine Drugs, Chinese Ministry of Education, Marine Drug and Food Institute, Ocean University of China.This study make preliminary evaluation about druggability on several novel modifiers of 18β-glycyrrhetinic acid and oleanolic acid on pharmacodynamics and pharmacokinetics.1. The pharmacodynamics on protective effects of novel modifiers of 18β-glycyrrhetic acid and oleanolic acid modifiers on carbon tetrachloride-induced liver injury in mice. The results displays that 18β-glycyrrhetic acid and oleanolic acid modifiers can depress markedly the numerical value of alanine minotransferase (ALT),asparatate aminotransferase (AST) and lactic dehydrogenase (LDH) in blood serum of mice caused by CCl4.18(3-glycyrrhetic acid and oleanolic acid modifiers also can depress markedly the content of malondisldehyde (MDA) in liver of mice caused by CCl4. They can boost markedly the numerical value of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in liver of mice caused by CCl4. The R configuration is similar with the S one. In a word,18β-glycyrrhetic acid and oleanolic acid modifiers can take the effect on protecting hepatic injury.2. The metabolism in vitro of 18β-glycyrrhetic acid and oleanolic acid modifiers is studied by the method of incubation in rats liver microsomes. The result displays that the tendency of metabolism in vitro about 18β-glycyrrhetic acid modifiers is as same as oleanolic acid modifiers. The concentration of modifiers diminish gradually as the time. The parent drugs are released in 30 min in the main. The concentration of parent drugs lower than the modifiers. The metabolism of the parent drugs progresses in the incubation in rats liver microsomes. The mechanisms of the metabolism in vitro of 18β-glycyrrhetic acid and oleanolic acid modifiers is that the modifiers is slowly converted to a ring-opened intermediate, which subsequently transformed by b-elimination reaction to a free phosphate. The free phosphate is further dephosphorylated by microsomal phosphatases, releasing the parent molecule with a free hydroxyl group.3. This paper establish the methods, which detect the concentratin of 18β-glycyrrhetic acid and oleanolic acid modifiers and parent drugs in rats blood, tissues and urine, feces.4. The plasma-concentration data are analyzed by compartmental in this paper. The modifiers and parent drugs belong to two-compartment model, which exist to 48h in rats. The t1/2 augments remarkably after i.p. and i.v. to rats. The parameter of pharmacokinetics are better than that administer the parent drugs directly. But the concentration of parent drugs is lower than modifiers.5. Both modifiers and parent drugs can also be detected in heart, liver, spleen, lung, kidney and brain. The concentration is the most highest in liver, which higher than that in blood. The results indicate that the novel modifiers have the effect of liver targeting. The organization cumulative toxicity dose not appear as the time. The R configuration is similar with the S one. The studies of 18β-glycyrrhetic acid and oleanolic acid modifiers take an important reference to clinic.6. The modifiers are mainly egested with feces in the form of archetype after intravenous 18β-glycyrrhetic acid and oleanolic acid modifiers to rats. The modifiers archetype also can be detected. The concentration of parent drugs released by modifiers is low that caused by metabolism of themselves. ConclusionsThe results of pharmacodynamics and pharmacokinetics display that the four modifiers can lessen the degree on carbon tetrachloride-induced liver injury in mice, which can elevate the half-life of parent drugs as a liver-targeted drugs.The preliminary evaluation indicates that both 18β-glycyrrhetic acid and oleanolic acid modifiers have the possible to be a medicine.