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Márton Jani - One of the best experts on this subject based on the ideXlab platform.
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Chlorothiazide is a substrate for the human uptake transporters OAT1 and OAT3
Journal of pharmaceutical sciences, 2013Co-Authors: Viktória Juhász, Erzsébet Beéry, Márton Jani, Zoltan K. Nagy, Annamária Bui, Éva D. Molnár, Joseph K. Zolnerciks, Rémi Magnan, Peter KrajcsiAbstract:ABSTRACT: The thiazide diuretic Chlorothiazide is poorly metabolized, and is predominantly excreted via the kidneys. We have previously shown that Chlorothiazide is transported by ATP-binding cassette transporter G2, suggesting a potential role for this transporter in apical efflux of Chlorothiazide in the kidney. However, because of the poor passive permeability of the drug, it is likely that uptake transporters on the basolateral membrane are also involved to facilitate vectorial transport in the renal proximal tubule. Two suggested candidate transporters for this role are the human organic anion transporters, OAT1 and OAT3. By using mammalian cells stably expressing these transporters, we have demonstrated OAT1- and OAT3-dependent uptake of Chlorothiazide with Michaelis constant values of 14.5 and 37.6 µM, respectively. Furthermore, we have found that probenecid, furosemide, and diclofenac inhibit Chlorothiazide transport by OAT1 and OAT3, of which the probenecide-mediated inhibition may be of clinical importance. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1683–1687, 2013
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abcg2 modulates Chlorothiazide permeability in vitro characterization of its interactions
Drug Metabolism and Pharmacokinetics, 2012Co-Authors: Erzsébet Beéry, Franciska Erdő, Zsuzsanna Rajnai, Tibor Abonyi, Ildikó Makai, Száva Bánsághi, István Sziráki, Emese Kis, Krisztina Herediszabo, Márton JaniAbstract:Summary: We are showing that Chlorothiazide, a diuretic, is an ABCG2 substrate. It is a Biopharmaceutics Classification System/Biopharmaceutics Drug Distribution and Classification System (BCS/BDDCS) Class IV drug with low bioavailability. Therefore, we tested if Chlorothiazide interacts with major apically located intestinal efflux transporters. Our data show that Chlorothiazide is transported by ABCG2 with a K m value of 334.6 μΜ and does not interact with ABCB1 or ABCC2. The Chlorothiazide–ABCG2 interaction results in a vectorial transport in MDCKII-BCRP and Caco-2 cells with efflux ratios of 36 and 8.1 respectively. Inhibition of ABCG2 in Caco-2 cells reduced the efflux ratio to 1.4, suggesting that ABCG2 plays a role in limiting Chlorothiazide bioavailability in humans.
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ABCG2 Modulates Chlorothiazide Permeability In Vitro–characterization of Its Interactions
Drug metabolism and pharmacokinetics, 2011Co-Authors: Erzsébet Beéry, Franciska Erdő, Zsuzsanna Rajnai, Tibor Abonyi, Ildikó Makai, Száva Bánsághi, István Sziráki, Krisztina Herédi-szabó, Emese Kis, Márton JaniAbstract:Summary: We are showing that Chlorothiazide, a diuretic, is an ABCG2 substrate. It is a Biopharmaceutics Classification System/Biopharmaceutics Drug Distribution and Classification System (BCS/BDDCS) Class IV drug with low bioavailability. Therefore, we tested if Chlorothiazide interacts with major apically located intestinal efflux transporters. Our data show that Chlorothiazide is transported by ABCG2 with a K m value of 334.6 μΜ and does not interact with ABCB1 or ABCC2. The Chlorothiazide–ABCG2 interaction results in a vectorial transport in MDCKII-BCRP and Caco-2 cells with efflux ratios of 36 and 8.1 respectively. Inhibition of ABCG2 in Caco-2 cells reduced the efflux ratio to 1.4, suggesting that ABCG2 plays a role in limiting Chlorothiazide bioavailability in humans.
Erzsébet Beéry - One of the best experts on this subject based on the ideXlab platform.
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Chlorothiazide is a substrate for the human uptake transporters OAT1 and OAT3
Journal of pharmaceutical sciences, 2013Co-Authors: Viktória Juhász, Erzsébet Beéry, Márton Jani, Zoltan K. Nagy, Annamária Bui, Éva D. Molnár, Joseph K. Zolnerciks, Rémi Magnan, Peter KrajcsiAbstract:ABSTRACT: The thiazide diuretic Chlorothiazide is poorly metabolized, and is predominantly excreted via the kidneys. We have previously shown that Chlorothiazide is transported by ATP-binding cassette transporter G2, suggesting a potential role for this transporter in apical efflux of Chlorothiazide in the kidney. However, because of the poor passive permeability of the drug, it is likely that uptake transporters on the basolateral membrane are also involved to facilitate vectorial transport in the renal proximal tubule. Two suggested candidate transporters for this role are the human organic anion transporters, OAT1 and OAT3. By using mammalian cells stably expressing these transporters, we have demonstrated OAT1- and OAT3-dependent uptake of Chlorothiazide with Michaelis constant values of 14.5 and 37.6 µM, respectively. Furthermore, we have found that probenecid, furosemide, and diclofenac inhibit Chlorothiazide transport by OAT1 and OAT3, of which the probenecide-mediated inhibition may be of clinical importance. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1683–1687, 2013
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abcg2 modulates Chlorothiazide permeability in vitro characterization of its interactions
Drug Metabolism and Pharmacokinetics, 2012Co-Authors: Erzsébet Beéry, Franciska Erdő, Zsuzsanna Rajnai, Tibor Abonyi, Ildikó Makai, Száva Bánsághi, István Sziráki, Emese Kis, Krisztina Herediszabo, Márton JaniAbstract:Summary: We are showing that Chlorothiazide, a diuretic, is an ABCG2 substrate. It is a Biopharmaceutics Classification System/Biopharmaceutics Drug Distribution and Classification System (BCS/BDDCS) Class IV drug with low bioavailability. Therefore, we tested if Chlorothiazide interacts with major apically located intestinal efflux transporters. Our data show that Chlorothiazide is transported by ABCG2 with a K m value of 334.6 μΜ and does not interact with ABCB1 or ABCC2. The Chlorothiazide–ABCG2 interaction results in a vectorial transport in MDCKII-BCRP and Caco-2 cells with efflux ratios of 36 and 8.1 respectively. Inhibition of ABCG2 in Caco-2 cells reduced the efflux ratio to 1.4, suggesting that ABCG2 plays a role in limiting Chlorothiazide bioavailability in humans.
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ABCG2 Modulates Chlorothiazide Permeability In Vitro–characterization of Its Interactions
Drug metabolism and pharmacokinetics, 2011Co-Authors: Erzsébet Beéry, Franciska Erdő, Zsuzsanna Rajnai, Tibor Abonyi, Ildikó Makai, Száva Bánsághi, István Sziráki, Krisztina Herédi-szabó, Emese Kis, Márton JaniAbstract:Summary: We are showing that Chlorothiazide, a diuretic, is an ABCG2 substrate. It is a Biopharmaceutics Classification System/Biopharmaceutics Drug Distribution and Classification System (BCS/BDDCS) Class IV drug with low bioavailability. Therefore, we tested if Chlorothiazide interacts with major apically located intestinal efflux transporters. Our data show that Chlorothiazide is transported by ABCG2 with a K m value of 334.6 μΜ and does not interact with ABCB1 or ABCC2. The Chlorothiazide–ABCG2 interaction results in a vectorial transport in MDCKII-BCRP and Caco-2 cells with efflux ratios of 36 and 8.1 respectively. Inhibition of ABCG2 in Caco-2 cells reduced the efflux ratio to 1.4, suggesting that ABCG2 plays a role in limiting Chlorothiazide bioavailability in humans.
Brent N Reed - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of intravenous Chlorothiazide versus oral metolazone in patients with acute decompensated heart failure and loop diuretic resistance
Pharmacotherapy, 2016Co-Authors: Christine E Shulenberger, Anthony Jiang, Sandeep Devabhakthuni, Vijay Ivaturi, Tao Liu, Brent N ReedAbstract:tudy Objective To assess the efficacy and safety of intravenous (IV) Chlorothiazide versus oral metolazone when added to loop diuretics in patients with acute decompensated heart failure (ADHF) and loop diuretic resistance. Design Retrospective cohort study. Setting Large urban academic medical center. Patients Adults admitted with ADHF between 2005 and 2015 who had loop diuretic resistance, defined as administration of IV furosemide at a dose of 160 mg/day or higher (or an equivalent dose of IV bumetanide), during hospitalization, and who then received at least one dose of IV Chlorothiazide (88 patients) or oral metolazone (89 patients) to augment diuresis. Measurements and Main Results The primary efficacy end point was a change in 24-hour net urine output (UOP) from before to after thiazide-type diuretic administration, and the study was designed to test for the noninferiority of metolazone. Safety end points included changes in renal function and electrolyte concentrations. The mean dose of IV loop diuretic therapy (in IV furosemide equivalents) at baseline (before thiazide-type diuretic administration) was higher in the Chlorothiazide group (mean ± SD 318.9 ± 127.7 vs 268.4 ± 97.6 mg/day in the metolazone group, p=0.004), but net UOP was similar (mean ± SD 877.0 ± 1189.0 ml in the Chlorothiazide group vs 710.6 ± 1145.9 ml in the metolazone group, p=0.344). Mean doses of Chlorothiazide and metolazone were 491 ± 282 mg and 5.8 ± 3.5 mg, respectively. Following thiazide-type diuretic administration, net UOP improved to a similar degree (2274.6 ± 1443.0 ml vs 2030.2 ± 1725.0 ml in the Chlorothiazide and metolazone groups, respectively, p=0.308). For the primary efficacy end point, metolazone met the threshold for noninferiority by producing a net UOP of 1319.6 ± 1517.4 ml versus 1397.6 ± 1370.7 ml for Chlorothiazide (p=0.026 for noninferiority). No significant differences in renal function were observed between the groups. Although hypokalemia was more frequent in the Chlorothiazide group (75% with Chlorothiazide vs 60.7% with metolazone, p=0.045), no significant differences in the rates of severe hypokalemia or other electrolyte abnormalities were observed between the groups. Conclusion Oral metolazone was noninferior to IV Chlorothiazide for enhancing net UOP in patients with ADHF and loop diuretic resistance and was similarly safe with regard to renal function and electrolyte abnormalities. Given the significant cost disparity between the two agents, these findings suggest that oral metolazone may be considered a first-line option in this patient population.
B. E. C. Nordin - One of the best experts on this subject based on the ideXlab platform.
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The effect of Chlorothiazide on bone-related biochemical variables in normal post-menopausal women
Journal of the American Geriatrics Society, 1993Co-Authors: C. A. Peh, Michael Horowitz, Judith M. Wishart, A. G. Need, Howard A. Morris, B. E. C. NordinAbstract:Objective To evaluate the effects of short-term administration of Chlorothiazide on fasting urinary hydroxyproline, an index of bone resorption, and other bone-related biochemical parameters in normal post-menopausal women. Design Subjects served as their own control before and after Chlorothiazide treatment. Setting Subjects were recruited by advertisement. Participants Thirteen healthy post-menopausal women with a mean age of 65 years. Intervention Each subject was given Chlorothiazide 500 mg bd po for 7 days. Fasting blood and urine samples were obtained immediately before the commencement of Chlorothiazide (day 1) and 2 and 7 days after starting Chlorothiazide. Results Chlorothiazide decreased the urinary calcium/creatinine (mean value day 1, 0.267; day 2, 0.143; day 7, 0.135; P < 0.001) and hydroxyproline/creatinine (day 1, 0.0192; day 2, 0.0145; day 7, 0.0139; P < 0.02) molar ratios. Conclusion Chlorothiazide decreases fasting urinary hydroxyproline, a marker of bone resorption in post-menopausal women. This observation supports a potential role for thiazide diuretics in the prevention of osteoporosis. The observed fall in urinary hydroxyproline is of the same order as that seen after treatment with estrogen or calcium supplements.
Peter A. Friedman - One of the best experts on this subject based on the ideXlab platform.
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Cellular mechanisms of Chlorothiazide and cellular potassium depletion on Mg2+ uptake in mouse distal convoluted tubule cells
Kidney international, 1997Co-Authors: Long-jun Dai, Peter A. FriedmanAbstract:Cellular mechanisms of Chlorothiazide and cellular potassium depletion on Mg 2+ uptake in mouse distal convoluted tubule cells. The use of the distally-acting diuretic, Chlorothiazide, has been reported to have important effects on renal magnesium handling. The cellular mechanisms of Chlorothiazide action on Mg 2+ uptake was investigated in immortalized mouse distal convoluted tubule (MDCT) cells. Intracellular free Mg 2+ concentration was determined by microfluorescence. Mg 2+ transport was measured as a function of change in intracellular Mg 2+ concentration with time following placement of Mg 2+ -depleted cells into a buffer containing 1.5mM magnesium. The uptake rate of Mg 2+ into Mg 2+ -depleted cells was 179 ± 28 nM/second. Mg 2+ uptake was dependent on the membrane voltage as membrane hyperpolarization enhanced uptake whereas depolarization diminished transport. Chlorothiazide increased Mg 2+ uptake by 58%, from 179 ± 28 to 283 ± 23 nM/second. The ability of Chlorothiazide to stimulate Mg 2+ uptake in MDCT cells was concentration-dependent and related to the diuretic-induced hyperpolarization of the plasma membrane. These studies support the notion that acute Chlorothiazide administration enhances renal magnesium conservation through its effects on Mg 2+ transport within the distal convoluted tubule. Since chronic Chlorothiazide administration may result in hypokalemia as well as hypomagnesemia, Mg 2+ uptake was determined in potassium-depleted MDCT cells. Mg 2+ uptake was diminished, 80 ± 24 nM/second, in potassium depleted cells. Hyperpolarization of the plasma membrane with the cell permanent anion, SCN − , corrected Mg 2+ uptake in potassium depleted cells suggesting that the basis for diminished uptake may, in part, be due to depolarization of the membrane voltage. In summary, acute Chlorothiazide stimulates Mg 2+ transport in MDCT cells. We postulate that chronic Chlorothiazide use may lead to hypokalemia that in turn diminishes Mg 2+ transport in the distal tubule resulting in urinary magnesium-wasting.