Determination of thermodynamic pKa values of benzimidazole and benzimidazole derivatives by capillary electrophoresis.
ABSTRACT Thermodynamic pK(a) values for benzimidazole and several substituted benzimidazoles were determined by CE. Electrophoretic mobilities of benzimidazoles were determined by CE at different pH levels and ionic strengths. The dependence of electrophoretic mobilities on pH was used to obtain pK(a) values at different ionic strengths. Extrapolations to zero ionic strength were used to determine the thermodynamic pK(a) values. Using this method the thermodynamic pK(a) values of 15 benzimidazoles were determined and found to range from 4.48 to 7.38. Results from the CE measurements were compared with spectrophotometric measurements which were evaluated at wavelengths where the highest absorbance difference for varying pH was recorded. The two analytical techniques were in good agreement.
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ABSTRACT: In this paper the validation of pKa determination in MDM-water mixtures is presented. The MDM-water mixture is a new multicomponent cosolvent mixture (consisting of equal volumes of methanol, dioxane and acetonitrile, as organic solvents) that dissolves a wide range of poorly water-soluble compounds. The cosolvent dissociation constants (p(s)Ka) of 50 chemically diverse compounds (acids, bases and ampholytes) were measured in 15-56 wt% MDM-water mixtures by potentiometric or spectrophotometric titration and the aqueous pKa values obtained by extrapolation. Three different extrapolation procedures were compared in order to choose the best extrapolation in MDM-water mixture using a sub-set of 30 water-soluble compounds. The extrapolated results are in good agreement with pKa values measured in aqueous medium. No significant difference was found among these extrapolation procedures thus the widely used Yasuda-Shedlovsky plot was proposed for MDM cosolvent also. Further we also present that the single point estimation based on measurement in 20%/v MDM-mixture using a general calibration equation may be suitable for rapid pKa determination in the early phase of drug research.Analytica chimica acta 03/2007; 583(2):418-28. · 4.31 Impact Factor
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ABSTRACT: In Japanese healthy CYP2C19 extensive metabolizers, rabeprazole 10 mg shows a faster onset of action and stronger inhibition of acid secretion than does omeprazole 20 mg on the first 3 days of administration. We evaluated gastric ulcer improvement after 1 week's treatment with rabeprazole or omeprazole in relation to CYP2C19 polymorphism. A 6-mm rubber disc was placed temporarily at the side of the ulcer for measurement of the ulcer area. The improvement ratios of ulcer area in homozygous extensive metabolizers (homoEMs), heterozygous extensive metabolizers (heteroEMs) and poor metabolizers (PMs) treated with rabeprazole 10 mg were 60.8, 65.0 and 55.3%, respectively, and these values are not significantly different. Corresponding values with omeprazole 20 mg were 46.3, 61.7 and 63.2%, respectively, and the value of homoEMs was significantly smaller than that of heteroEMs. The improvement ratios with rabeprazole in homoEMs and heteroEMs were significantly greater than that with omeprazole in homoEMs.Digestive Diseases and Sciences 05/2008; 53(4):933-7. · 2.26 Impact Factor
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ABSTRACT: Methylcarbamate benzimidazoles [albendazole (ABZ), fenbendazole (FBZ), and their respective sulfoxide derivatives, albendazole sulfoxide (ABZSO) and oxfendazole (OXF)] are therapeutically important anthelmintic agents with low bioavailability. We studied their in vitro interaction with the apical ATP-binding cassette (ABC) drug efflux transporters, breast cancer resistance protein (BCRP/ABCG2), P-glycoprotein (ABCB1), and MRP2 (ABCC2) using MDCKII cells transduced with human MDR1, MRP2, and BCRP, and murine Bcrp1 cDNAs. These ABC drug efflux transporters extrude a wide range of xenotoxins from cells in intestine, liver, and other organs, thus affecting the bioavailability of many compounds. In transport experiments, ABZSO and OXF were transported efficiently by murine Bcrp1 and moderately by human BCRP, but not by MDR1 or MRP2. ABZ and FBZ were not found to be Bcrp1, MRP2, or P-glycoprotein substrates in vitro. OXF was found to be a good BCRP/Bcrp1 inhibitor, with somewhat higher potency in the MDCKII-BCRP cell line. The latter results were confirmed by flow cytometry experiments demonstrating inhibition by OXF of murine Bcrp1- and human BCRP-mediated mitoxantrone transport. Further studies of interactions between OXF and known BCRP/Bcrp1 substrates will be of interest. The use of efficacious BCRP/Bcrp1 inhibitors might increase the extent and duration of systemic exposure to ABZSO and OXF, with possible therapeutically beneficial effects in extra-intestinal infections.Drug Metabolism and Disposition 06/2005; 33(5):614-8. · 3.36 Impact Factor