3612-80-4Relevant academic research and scientific papers
Predictions of stability in pharmaceutical preparations XIX: Stability evaluation and bioanalysis of clofibric acid esters by high-pressure liquid chromatography.
Garrett,Gardner
, p. 14 - 25 (1982)
Specific, sensitive, reversed-phase high-pressure liquid chromatographic assays of clofibric acid esters, clofibrate and etofibrate, and their hydrolysis products, clofibric acid and its monoglycolate and nicotinic acid and its monoglycolate, have been developed in aqueous solution and in biological fluids. Sensitivities of 100 ng/ml of injected mobile phase, a 10-fold increase over existing methods, are reported. Plasma concentrations as low as 200 ng/ml can be analyzed easily in the miscible phase after acetonitrile denaturation. The compounds and their products can be extracted with haloalkane solvents. The extracts were evaporated, reconstituted, and assayed in minimal amounts of mobile phase, resulting in sensitivities of 10 ng/ml of plasma. Conditions are presented that minimize interferences with plasma components. The assay was used to determine the stability of the clofibric acid esters in aqueous solutions, to establish log k-pH profiles at various temperatures, and to evaluate Arrhenius parameters. Hydrolysis was by specific acid-base catalysis. The initial product of etofibrate solvolysis at pH greater than 6 is the monoglycol ester of clofibric acid; at pH less than 3, it is the monoglycol ester of nicotinic acid. Clofibric acid esters are highly unstable to mild alkali (1-3 hr at pH 10 and 30 degrees); even in the estimated pH range of maximum stability, they have half-lives of 100-200 days at 30 degrees. They have half-lives of 4-7 min at 37.5 degrees in fresh dog plasma, and data presented indicate that clofibric acid monoglycolate is an initial product of etofibrate solvolysis.
Synthesis, characterization and in vitro hydrolysis of a gemfibrozil-nicotinic acid codrug for improvement of lipid profile
Qandil, Amjad M.,Rezigue, Meriem M.,Tashtoush, Bassam M.
experimental part, p. 99 - 108 (2012/03/11)
Combination therapy of fibrates and nicotinic acid has been reported to be synergistic. Herein, we describe a covalent codrug of gemfibrozil (GEM) and nicotinic acid (NA) that was synthesized and characterized by 1H NMR, 13C NMR, FT-IR, MS analysis and elemental analysis. A validated HPLC method was developed that allows for the accurate quantitative determination of the codrug and its hydrolytic products that are formed during the in vitro chemical and enzymatic hydrolysis. The physico-chemical properties of codrug were improved compared to its parent drugs in term of water solubility and partition coefficient. The kinetics of hydrolysis of the codrug was studied using accelerated hydrolysis experiments at high temperatures in aqueous phosphate buffer solution in pH 1.2, 6.8 and 7.4. Using the Arrhenius equation, the extrapolated half-life at 37°C were 289 days at pH 1.2 for the codrug and 130 and 20,315 days at pH 6.8 for the codrug and gemfibrozil 2-hydroxyethyl ester (GHEE), respectively. The shortest half-lives were at pH 7.4; 42 days for the codrug and 5837 days for GHEE, respectively. The hydrolysis of the latter was studied, alone, at 80°C and pH 1.2 and compared to its hydrolysis when it is produced from the codrug using similar conditions. The kobs was found in both cases to be 1.60 × 10-3 h-1. The half-lives in plasma were 35.24 min and 26.75 h for the codrug and GHEE, respectively. With regard to liver homogenate, the hydrolysis half-lives were 1.96 min and 48.13 min for the codrug and GHEE, respectively. It can be expected that in vivo, the codrug will liberate NA immediately in plasma then GEM will be liberated from its 2-hydroxyethyl ester in the liver.
Disposition of etofibrate, clofibric and nicotinic acid esters, and their products in dogs
Garrett,Altmayer
, p. 295 - 299 (2007/10/02)
Etofibrate, the ethylene glycol diester of clofibric and nicotinic acids, on intravenous infusion into dogs, has a terminal half-life of 2 min. The intermediate half-esters, the nicotinate and the clofibrate, have respective terminal half-lives of 4.6 and 1.7 min and appear fleetingly when etofibrate is administered. In contrast to the 42-h terminal half-life of clofibric acid, the other final transformation product, nicotinic acid, shows saturable or dose-dependent pharmacokinetics in dogs that conform to the Michaelis-Menten equation with a terminal half-life of 4.4 min at low concentrations ( 6.9 μM/kg). Three distinct metabolites of nicotinic acid can be identified and assayed chromatographically in the urine. The partition properties were similar to nicotinic acid. Nicotinic acid is excreted 30% unchanged into urine with a renal clearance of 70 mL/min in 27-kg dogs.
