-
Biochemical Pharmacology Nov 2014Human pregnane X receptor (hPXR) regulates the expression of drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) and drug transporters such as multidrug-resistance...
Human pregnane X receptor (hPXR) regulates the expression of drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) and drug transporters such as multidrug-resistance protein 1 (MDR1). PXR can be modulated by small molecules, including Federal Drug Administration (FDA)-approved drugs, thus altering drug metabolism and causing drug-drug interactions. To determine the role of FDA-approved drugs in PXR-mediated regulation of drug metabolism and clearance, we screened 1481 FDA-approved small-molecule drugs by using a luciferase reporter assay in HEK293T cells and identified the diuretic drug metolazone as an activator of hPXR. Our data showed that metolazone activated hPXR-mediated expression of CYP3A4 and MDR1 in human hepatocytes and intestine cells and increased CYP3A4 promoter activity in various cell lines. Mammalian two-hybrid assays showed that hPXR recruits its co-activator SRC-1 upon metolazone binding in HepG2 cells, explaining the mechanism of hPXR activation. To understand the role of other commonly-used diuretics in hPXR activation and the structure-activity relationship of metolazone, thiazide and non-thiazide diuretics drugs were also tested but only metolazone activates hPXR. To understand the molecular mechanism, docking studies and mutational analysis were carried out and showed that metolazone binds in the ligand-binding pocket and interacts with mostly hydrophobic amino acid residues. This is the first report showing that metolazone activates hPXR. Because activation of hPXR might cause drug-drug interactions, metolazone should be used with caution for drug treatment in patients undergoing combination therapy.
Topics: Cell Survival; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Diuretics; Dose-Response Relationship, Drug; HEK293 Cells; Hep G2 Cells; Humans; Metolazone; Multidrug Resistance-Associated Proteins; Pregnane X Receptor; Protein Binding; Receptors, Steroid; Thiazides
PubMed: 25181459
DOI: 10.1016/j.bcp.2014.08.025 -
BMC Pharmacology & Toxicology Nov 2017Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters.
METHODS
An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams.
RESULTS
Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed.
CONCLUSIONS
Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The t of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study.
TRIAL REGISTRATION
This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).
Topics: Administration, Oral; Adolescent; Adult; Antihypertensive Agents; Area Under Curve; Asian People; Diuretics; Drug Administration Schedule; Female; Food-Drug Interactions; Half-Life; Healthy Volunteers; Humans; Male; Metolazone; Tablets; Young Adult
PubMed: 29145890
DOI: 10.1186/s40360-017-0178-x -
Frontiers in Pharmacology 2022A network meta-analysis (NMA) of the current recommended drugs for the treatment of acute heart failure (AHF), was performed to compare the relative efficacy. We used... (Review)
Review
A network meta-analysis (NMA) of the current recommended drugs for the treatment of acute heart failure (AHF), was performed to compare the relative efficacy. We used PubMed, EMBASE, Cochrane Clinical Trials Register, and Web of Science systems to search studies of randomized controlled trials (RCT) for the treatment of AHF recommended by the guidelines and expert consensus until 1 December 2020. The primary outcome was all-cause mortality within 30 days. The secondary outcomes included 30-days all-cause rehospitalization, rates of HF-related rehospitalization, rates of adverse events, and rates of serious adverse events. A Bayesian NMA based on random effects model was performed. After screening 14,888 citations, 23 RCTs (17,097 patients) were included, focusing on nesiritide, placebo, serelaxin, rhANP, omecamtiv mecarbil, tezosentan, KW-3902, conivaptan, tolvaptan, TRV027, chlorothiazide, metolazone, ularitide, relaxin, and rolofylline. Omecamtiv mecarbil had significantly lower all-cause mortality rates than the placebo (odds ratio 0.04, 0.01-0.22), rhANP (odds ratio 0.03, 0-0.40), serelaxin (odds ratio 0.05, 0.01-0.38), tezosentan (odds ratio 0.04, 0-0.22), tolvaptan (odds ratio 0.04, 0.01-0.30), and TRV027 (odds ratio 0.03, 0-0.36). No drug was superior to the other drugs for the secondary outcomes and safety outcomes. No drug was superior to the other drugs for the secondary outcomes and safety outcomes. Current drugs for AHF show similar efficacy and safety.
PubMed: 36210851
DOI: 10.3389/fphar.2022.677589 -
Clinical Journal of the American... Sep 2017Several drugs used in CKD can prolong electrocardiographic conduction. We examined the use of electrocardiogram QT-prolonging medications in predialysis CKD and their...
BACKGROUND AND OBJECTIVES
Several drugs used in CKD can prolong electrocardiographic conduction. We examined the use of electrocardiogram QT-prolonging medications in predialysis CKD and their association with QT duration.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
In total, 3252 Chronic Renal Insufficiency Cohort participants with at least one study electrocardiogram between 2003 and 2011 were included. QT-prolonging medications used in 100 or more visits (=16,451 visits) along with diuretics and proton pump inhibitors, given their potential for electrolyte disturbances, were examined for QT interval prolongation.
RESULTS
Mean QT interval corrected for heart rate was at 414±21 (±SD) milliseconds and prolonged (≥450 milliseconds) in 4.6% of electrocardiograms. QT interval corrected for heart rate was inversely related to serum potassium and calcium. Medications classified as QT prolonging were taken at 76% of visits, with two or more of these taken at 33% of visits. Of 30 medications examined, eight were associated with statistically significant QT interval corrected for heart rate prolongation after adjustment for comorbidities, potassium, and calcium, including amiodarone (+10±2 milliseconds), metolazone (+7±2 milliseconds), fluoxetine (+4±1 milliseconds), citalopram (+4±1 milliseconds), hydroxyzine (+4±1 milliseconds), escitalopram (+3±2 milliseconds), venlafaxine (+3±1 milliseconds), and furosemide (+3±0 milliseconds). Potassium-depleting diuretics were associated with minimal decrements in potassium (between 0.1 and 0.3 mEq/L) and smaller changes in calcium. Diuretics associated with a change in QT interval corrected for heart rate before adjustment for potassium and calcium were metolazone (+8±3 milliseconds), furosemide (+4±1 milliseconds), and spironolactone (-3±3 milliseconds). Most of the QT prolongation associated with metolazone and furosemide, but not spironolactone, remained after adjustment for potassium and calcium. Proton pump inhibitors were not associated with QT prolongation.
CONCLUSIONS
Use of medications associated with QT prolongation is common in CKD; the safety implications of these findings should be considered in these high-risk patients.
PODCAST
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_09_CJASNPodcast_17_09_b.mp3.
Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Antidepressive Agents, Second-Generation; Citalopram; Diabetes Complications; Diuretics; Electrocardiography; Female; Fluoxetine; Furosemide; Heart; Heart Rate; Histamine H1 Antagonists; Humans; Hydroxyzine; Male; Metolazone; Middle Aged; Proton Pump Inhibitors; Renal Insufficiency, Chronic; Venlafaxine Hydrochloride
PubMed: 28793999
DOI: 10.2215/CJN.12991216 -
European Journal of Heart Failure Mar 2005This article examines the emerging role of the heart failure nurse and the responsibilities and educational and training requirements surrounding such a role. There may... (Review)
Review
This article examines the emerging role of the heart failure nurse and the responsibilities and educational and training requirements surrounding such a role. There may be variations in the role and its responsibilities in different health care settings. However the principles are similar and include: history taking, carrying out clinical assessment and making appropriate decisions about patient management within the context of practice. An example of this is nurse supervision of adjusting and titration of medication in a clinic setting or in the patient's own home. A major challenge to this role is defining the limitations and scope of practice. Patients with chronic heart failure (CHF) are generally a frail, elderly population, and often have significant other co-morbidities. They can be on multiple medications and are frequently prescribed sub-optimal doses of evidence-based medication. Many patients are not managed by specialists, thus creating a huge potential for improved management.
Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzothiadiazines; Comorbidity; Diuretics; Heart Failure; Humans; Metolazone; Nurse Clinicians; Nurse Practitioners; Nurse's Role; Practice Guidelines as Topic; Sodium Chloride Symporter Inhibitors; Spironolactone
PubMed: 15718175
DOI: 10.1016/j.ejheart.2005.01.005 -
Cardiovascular Therapeutics Apr 2015Sequential nephron blockade with thiazide-like diuretics is a strategy used to overcome diuretic resistance in acute decompensated heart failure (ADHF), but head-to-head... (Comparative Study)
Comparative Study
AIMS
Sequential nephron blockade with thiazide-like diuretics is a strategy used to overcome diuretic resistance in acute decompensated heart failure (ADHF), but head-to-head studies are lacking and equipoise exists regarding the preferred thiazide-like diuretic in this setting. We thus compared the effectiveness of oral metolazone versus intravenous (IV) chlorothiazide as add-on therapy to loop diuretics in hospitalized patients with ADHF and renal dysfunction.
METHODS
This retrospective cohort study evaluated the efficacy and safety of oral metolazone versus IV chlorothiazide as add-on therapy to loop diuretics in patients hospitalized with ADHF and renal dysfunction. The primary endpoint was net urine output (UOP) at 72 h after initiation of thiazide-like diuretics. Safety endpoints included worsening renal function, hypotension, and electrolyte abnormalities.
RESULTS
Fifty-five patients were enrolled with 33 patients receiving metolazone and 22 patients receiving chlorothiazide. There was no difference in median net UOP at 72 h in those receiving metolazone (4828 mL, interquartile range [IQR] 2800-7209 mL) compared to chlorothiazide (3779 mL, IQR 1885-6535 mL) (P = 0.16). There was no difference in hypotension, worsening renal function, hyponatremia, or hypokalemia (P = NS for all comparisons). Hospital length of stay was shorter in the metolazone cohort (median 7 days) compared to chlorothiazide (median 15 days), suggesting the chlorothiazide cohort was likely sicker.
CONCLUSION
Sequential nephron blockade with either metolazone or chlorothiazide appears to be efficacious and safe in ADHF, renal dysfunction, and diuretic resistance. Given the considerable cost difference favoring oral metolazone, larger randomized studies are warranted to confirm our findings and to exclude the possibility of confounding by indication.
Topics: Acute Disease; Administration, Intravenous; Administration, Oral; Aged; Chicago; Chlorothiazide; Drug Resistance; Drug Therapy, Combination; Female; Heart Failure; Hospitalization; Humans; Length of Stay; Male; Metolazone; Middle Aged; Nephrons; Retrospective Studies; Sodium Chloride Symporter Inhibitors; Sodium Potassium Chloride Symporter Inhibitors; Time Factors; Treatment Outcome; Urination
PubMed: 25712736
DOI: 10.1111/1755-5922.12109 -
Molecules (Basel, Switzerland) Jul 2019This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical...
This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (C), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their C and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its C and AUC by 50%, with C being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.
Topics: Calorimetry, Differential Scanning; Chemical Phenomena; Crystallization; Drug Stability; Kinetics; Pharmaceutical Preparations; Preservation, Biological; Solubility; Spectrum Analysis, Raman; Time Factors
PubMed: 31357587
DOI: 10.3390/molecules24152731 -
PloS One 2021Twelve carbonic anhydrase (CA) isoforms catalyze carbon dioxide hydration to bicarbonate and acid protons and are responsible for many biological functions in human...
Twelve carbonic anhydrase (CA) isoforms catalyze carbon dioxide hydration to bicarbonate and acid protons and are responsible for many biological functions in human body. Despite their vital functions, they are also responsible for, or implicated in, numerous ailments and diseases such as glaucoma, high altitude sickness, and cancer. Because CA isoforms are highly homologous, clinical drugs designed to inhibit enzymatic activity of a particular isoform, can also bind to others with similar affinity causing toxic side effects. In this study, the affinities of twelve CA isoforms have been determined for nineteen clinically used drugs used to treat hypertension related diseases, i.e. thiazides, indapamide, and metolazone. Their affinities were determined using a fluorescent thermal shift assay. Stopped flow assay and isothermal titration calorimetry were also employed on a subset of compounds and proteins to confirm inhibition of CA enzymatic activity and verify the quantitative agreement between different assays. The findings of this study showed that pharmaceuticals could bind to human CA isoforms with variable affinities and inhibit their catalytic activity, even though the drug was intended to interact with a different (non-CA) protein target. Relatively minor structural changes of the compounds may cause significant changes in affinity and selectivity for a particular CA isoform.
Topics: Carbonic Anhydrases; Catalytic Domain; Humans; Isoenzymes; Protein Binding; Structure-Activity Relationship; Sulfonamides; Thiazides; Benzenesulfonamides
PubMed: 34166457
DOI: 10.1371/journal.pone.0253608 -
Journal of Controlled Release :... Jun 2017We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a...
We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a small-scale dissolution apparatus (μDISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This protocol then guided how to stabilize the amorphous formulation. Indapamide, metolazone, glibenclamide and glipizide were selected as model drugs and HPMC (Pharmacoat 606) and PVP (K30) as stabilizing polymers. Spray-dried amorphous indapamide, metolazone and glibenclamide crystallized via solution-mediated nucleation while glipizide suffered from solid-to-solid crystallization. The addition of 0.001%-0.01% (w/v) HPMC into the dissolution medium successfully prevented the crystallization of supersaturated solutions of indapamide and metolazone whereas it only reduced the crystallization rate for glibenclamide. Amorphous solid dispersion (ASD) formulation of glipizide and PVP K30, at a ratio of 50:50% (w/w) reduced but did not completely eliminate the solid-to-solid crystallization of glipizide even though the overall dissolution rate was enhanced both in the absence and presence of HPMC. Raman spectroscopy indicated the formation of a glipizide polymorph in the dissolution medium with higher solubility than the stable polymorph. As a complementary technique, molecular dynamics (MD) simulations of indapamide and glibenclamide with HPMC was performed. It was revealed that hydrogen bonding patterns of the two drugs with HPMC differed significantly, suggesting that hydrogen bonding may play a role in the greater stabilizing effect on supersaturation of indapamide, compared to glibenclamide.
Topics: Calorimetry, Differential Scanning; Crystallization; Drug Compounding; Drug Liberation; Drug Stability; Glipizide; Glyburide; Hydrogen Bonding; Hypromellose Derivatives; Indapamide; Metolazone; Molecular Dynamics Simulation; Povidone; Spectrum Analysis, Raman
PubMed: 28412224
DOI: 10.1016/j.jconrel.2017.04.015 -
Critical Care Research and Practice 2021One of the strategies for overcoming diuretic resistance among heart failure (HF) patients is adding thiazide-type diuretics. The main aim of this article is to compare...
BACKGROUND
One of the strategies for overcoming diuretic resistance among heart failure (HF) patients is adding thiazide-type diuretics. The main aim of this article is to compare the adverse clinical outcomes, including death and re-hospitalization, among individuals suffering from severe acute decompensated HF (ADHF) that consumed furosemide or furosemide plus metolazone.
METHODS
This retrospective cohort study was done in the context of the Persian registry of cardiovascular disease (PROVE) from September 2017 to September 2018. One thousand and four hundred thirty-eight individuals (furosemide: 972 and furosemide plus metolazone: 466) with the final diagnosis of severe ADHF (left ventricular ejection fraction < 30%) were selected and followed for 10.3 ± 7.8 months. The association between two groups, as mentioned above, with the incidence of death and re-admission, was evaluated with different models.
RESULTS
The mean age of the study population was 68.19 ± 12.98 years. There was no significant relation in terms of death or re-hospitalization between patients with different diuretic regimens. After adjustment of potential confounders, we found that adding metolazone as an adjuvant HF therapy was not independently associated with death or re-hospitalization (hazard ratio (HR): 0.78,95% confidence interval (CI) = 0.59-1.03, = 0.085, and odds ratio (OR): 0.80, 95% CI: 0.60-1.07, = 0.135, respectively).
CONCLUSION
Our findings revealed that adding metolazone in patients with furosemide resistance is not associated with higher morbidity and mortality. Therefore, usage of these two therapeutic agents could be a helpful strategy for severe HF patients.
PubMed: 34721901
DOI: 10.1155/2021/3820292