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1.
BMC Pharmacol Toxicol ; 22(1): 34, 2021 06 13.
Article in English | MEDLINE | ID: mdl-34120651

ABSTRACT

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are characterized by an elevated glycemic index and are at a higher risk for complications such as cardiovascular disease, nephropathy, retinopathy and peripheral neuropathy. Normalization of glycemic index can be achieved by dosing combinations of metformin with other anti-diabetic drugs. The present study (Clintrials number NCT00519480) was conducted to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of remogliflozinetabonate, an SGLT2 inhibitor, withdoses (500 mg and 750 mg BID) greater than the commercial dose (100 mg BID)in combination with metformin with minimum daily dose of 2000 mg given in two divided doses. METHODS: This was a randomized, double-blinded, repeat dose study in 50 subjects with T2DM. The study was conducted in three phases; run-in, randomization, and treatment. All subjects were on a stable metformin dosing regimen. Cohort 1 subjects were randomly allocated to receive either remogliflozin etabonate 500 mg BID or placebo BID (2:1) in addition to metformin. Cohort 2 subjects were administered with either remogliflozin etabonate 750 mg BID or placebo BID (2:1) in addition to metformin for 13 days. All the subjects were assessed for safety (adverse events, lactic acid levels, vital signs, electrocardiogram [ECG]), pharmacokinetic evaluation, and pharmacodynamics (Oral Glucose Tolerance Testing) parameters. RESULTS: Co-administration of remogliflozin etabonate and metformin was well tolerated in all subjects during the observation period. There were no severe or serious adverse events (SAEs) and no increase in lactic acid concentration was reported during the study. The statistical results showed that concomitant administration of remogliflozin etabonate, either 500 mg or 750 mg BID, with metformin had no effect on the pharmacokinetics of metformin. The accumulation ratios, Day 13 vs. Day 1, for AUC values of remogliflozin etabonate and its metabolites were all very close to 1, indicating no accumulation in plasma concentrations of remogliflozin etabonate and its metabolites. Mean glucose values from baseline and glucose and insulin values following oral glucose tolerance test (OGTT) were decreased in all treatment groups. CONCLUSION: Co-administration of doses of remogliflozin etabonate (500 mg BID or 750 mg BID) greater than the commercial dose (100 mg BID) with metformin (2000 mg BID) was shown to be safe and effective during the observation period. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00519480 . Registered:22 August 2007.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucosides/administration & dosage , Hypoglycemic Agents/administration & dosage , Metformin/administration & dosage , Pyrazoles/administration & dosage , Adult , Blood Glucose/drug effects , Blood Pressure/drug effects , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/metabolism , Double-Blind Method , Drug Interactions , Drug Therapy, Combination , Fasting/blood , Fasting/metabolism , Female , Glucosides/adverse effects , Glucosides/pharmacokinetics , Humans , Hypoglycemic Agents/adverse effects , Insulin/blood , Lactic Acid/blood , Male , Metformin/adverse effects , Metformin/pharmacokinetics , Middle Aged , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics
2.
Drug Metab Dispos ; 43(7): 1077-83, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25934577

ABSTRACT

Remogliflozin etabonate (RE), the prodrug of remogliflozin, is an inhibitor of the sodium glucose-dependent renal transporter 2 (SGLT2), enabling urinary glucose excretion to reduce hyperglycemia for the treatment of type 2 diabetes. Renal function declines more rapidly in patients with type 2 diabetes, making it difficult or unsafe to continue on some antidiabetic therapeutics. In an initial effort to understand the potential utility of RE in patients with renal impairment, the pharmacodynamics and pharmacokinetics of RE were evaluated in a single oral dose (250 mg) in patients with renal impairment as compared with control subjects. As shown by pharmacodynamic measurements of urinary glucose excretion, there was no clinically significant reduction in the ability of remogliflozin to inhibit SGLT2. In addition, there were no significant changes in area under the curve (from 0 to infinity) or half-life of remogliflozin, suggesting renal impairment does not alter the pharmacokinetics of remogliflozin. In contrast to other SGLT2 inhibitors which accumulate in patients with renal impairment, adjustment of the dosage of RE in subjects with mild or moderate renal impairment is not indicated based on the observations in this study.


Subject(s)
Glucosides/pharmacology , Glucosides/pharmacokinetics , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/pharmacokinetics , Kidney Diseases/metabolism , Pyrazoles/pharmacology , Pyrazoles/pharmacokinetics , Sodium-Glucose Transporter 2 Inhibitors , Adult , Aged , Area Under Curve , Female , Glucosides/adverse effects , Glycosuria/metabolism , Half-Life , Humans , Hypoglycemic Agents/adverse effects , Male , Middle Aged , Pyrazoles/adverse effects , Sodium-Glucose Transporter 2
3.
BMC Pharmacol Toxicol ; 14: 25, 2013 Apr 30.
Article in English | MEDLINE | ID: mdl-23631443

ABSTRACT

BACKGROUND: The sodium-dependent glucose co-transporter-2 (SGLT2) is expressed in absorptive epithelia of the renal tubules. Remogliflozin etabonate (RE) is the prodrug of remogliflozin, the active entity that inhibits SGLT2. An inhibitor of this pathway would enhance urinary glucose excretion (UGE), and potentially improve plasma glucose concentrations in diabetic patients. RE is intended for use for the treatment of type 2 diabetes mellitus (T2DM) as monotherapy and in combination with existing therapies. Metformin, a dimethylbiguanide, is an effective oral antihyperglycemic agent widely used for the treatment of T2DM. METHODS: This was a randomized, open-label, repeat-dose, two-sequence, cross-over study in 13 subjects with T2DM. Subjects were randomized to one of two treatment sequences in which they received either metformin alone, RE alone, or both over three, 3-day treatment periods separated by two non-treatment intervals of variable duration. On the evening before each treatment period, subjects were admitted and confined to the clinical site for the duration of the 3-day treatment period. Pharmacokinetic, pharmacodynamic (urine glucose and fasting plasma glucose), and safety (adverse events, vital signs, ECG, clinical laboratory parameters including lactic acid) assessments were performed at check-in and throughout the treatment periods. Pharmacokinetic sampling occurred on Day 3 of each treatment period. RESULTS: This study demonstrated the lack of effect of RE on steady state metformin pharmacokinetics. Metformin did not affect the AUC of RE, remogliflozin, or its active metabolite, GSK279782, although Cmax values were slightly lower for remogliflozin and its metabolite after co-administration with metformin compared with administration of RE alone. Metformin did not alter the pharmacodynamic effects (UGE) of RE. Concomitant administration of metformin and RE was well tolerated with minimal hypoglycemia, no serious adverse events, and no increase in lactic acid. CONCLUSIONS: Coadministration of metformin and RE was well tolerated in this study. The results support continued development of RE as a treatment for T2DM. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00376038.


Subject(s)
Glucosides/administration & dosage , Hypoglycemic Agents/administration & dosage , Metformin/administration & dosage , Prodrugs/administration & dosage , Pyrazoles/administration & dosage , Adult , Blood Glucose/analysis , Cross-Over Studies , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/urine , Female , Glucosides/blood , Glucosides/pharmacokinetics , Glycosuria , Humans , Hypoglycemic Agents/blood , Hypoglycemic Agents/pharmacokinetics , Male , Metformin/blood , Metformin/pharmacokinetics , Middle Aged , Prodrugs/pharmacokinetics , Pyrazoles/blood , Pyrazoles/pharmacokinetics , Sodium-Glucose Transporter 2 , Sodium-Glucose Transporter 2 Inhibitors
4.
BMC Pharmacol Toxicol ; 14: 26, 2013 May 13.
Article in English | MEDLINE | ID: mdl-23668634

ABSTRACT

BACKGROUND: Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans. METHODS: This double-blind, randomized, placebo-controlled, single-dose, dose-escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo separated by approximately 2 week intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg, or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clinical trials data base with identifier NCT01571661. RESULTS: RE was generally well-tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to maximum plasma concentration [Cmax;Tmax] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T½ of ~25 min; mean plasma T½ for remogliflozin was 120 min) and was independent of dose. All subjects showed dose-dependent increases in 24-hour UGE, which plateaued at approximately 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug-dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes. CONCLUSIONS: The results support progression of RE as a potential treatment for T2DM. TRIAL REGISTRATION: ClinicalTrials.gov NCT01571661.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glucosides/therapeutic use , Pyrazoles/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors , Adult , Area Under Curve , Blood Glucose/metabolism , Cross-Over Studies , Diabetes Mellitus, Type 2/metabolism , Diarrhea/chemically induced , Dizziness/chemically induced , Dose-Response Relationship, Drug , Double-Blind Method , Electrolytes/urine , Female , Glucosides/adverse effects , Glucosides/pharmacokinetics , Headache/chemically induced , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Insulin/blood , Male , Metabolic Clearance Rate , Middle Aged , Molecular Structure , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Sodium-Glucose Transporter 2/metabolism , Treatment Outcome
5.
Biopharm Drug Dispos ; 34(2): 79-86, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23111980

ABSTRACT

Remogliflozin etabonate (RE) is the prodrug of remogliflozin (R), an inhibitor of renal glucose transport designed to reduce blood glucose concentrations for the treatment of type 2 diabetes. This open-label, randomized, single-dose, four-way crossover study, (with one add-on arm) in eight healthy men evaluated the regional gastrointestinal absorption of RE, the systemic appearance of the active entity R, and an active metabolite, GSK279782. The InteliSite(®) Companion Capsule was used to administer a single dose of RE 100 mg to the mid-small intestine or cecum/colon. Oral administration of the IR tablet of RE showed similar bioavailability of R compared with small intestine delivery with both suspension and solution. The lowest bioavailability of remogliflozin was found with large intestine delivery and therefore not a suitable region for prodrug delivery. Although both lower permeability and decreased ester hydrolysis of remogliflozin etabonate in the colon can explain reduced plasma exposures of remogliflozin, the data suggest relatively limited remogliflozin etabonate hydrolysis in the colon and provides evidence for a diminishing gradient of esterase activity from small to large intestine.


Subject(s)
Gastrointestinal Tract/metabolism , Glucosides/pharmacokinetics , Hypoglycemic Agents/pharmacokinetics , Pyrazoles/pharmacokinetics , Administration, Oral , Adult , Biological Availability , Capsules , Cross-Over Studies , Glucosides/administration & dosage , Glucosides/blood , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/blood , Intestinal Absorption , Male , Middle Aged , Pyrazoles/administration & dosage , Pyrazoles/blood , Young Adult
6.
Diabetes Care ; 35(11): 2198-200, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23011728

ABSTRACT

OBJECTIVE: Remogliflozin etabonate (RE), an inhibitor of the sodium-glucose transporter 2, improves glucose profiles in type 2 diabetes. This study assessed safety, tolerability, pharmacokinetics, and pharmacodynamics of RE in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: Ten subjects managed with continuous subcutaneous insulin infusion were enrolled. In addition to basal insulin, subjects received five randomized treatments: placebo, prandial insulin, 50 mg RE, 150 mg RE, and mg RE 500. RESULTS: Adverse events and incidence of hypoglycemia with RE did not differ from placebo and prandial insulin groups. RE significantly increased urine glucose excretion and reduced the rise in plasma glucose concentration after oral glucose. RE reduced incremental adjusted weighted mean glucose (0-4 h) values by 42-49 mg/dL and mean glucose (0-10 h) by 52-69 mg/dL. CONCLUSIONS: RE can be safely administered with insulin in type 1 diabetes and reduces plasma glucose concentrations compared with placebo.


Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 1/drug therapy , Glucosides/therapeutic use , Hypoglycemic Agents/therapeutic use , Pyrazoles/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors , Adult , Diabetes Mellitus, Type 1/blood , Female , Glucosides/administration & dosage , Humans , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Insulin/therapeutic use , Male , Middle Aged , Pyrazoles/administration & dosage
7.
Drug Metab Dispos ; 40(11): 2090-101, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22851617

ABSTRACT

Remogliflozin etabonate is the ester prodrug of remogliflozin, a selective sodium-dependent glucose cotransporter-2 inhibitor. This work investigated the absorption, metabolism, and excretion of [(14)C]remogliflozin etabonate in humans, as well as the influence of P-glycoprotein (Pgp) and cytochrome P450 (P450) enzymes on the disposition of remogliflozin etabonate and its metabolites to understand the risks for drug interactions. After a single oral 402 ± 1.0 mg (106 ± 0.3 µCi) dose, [(14)C]remogliflozin etabonate is rapidly absorbed and extensively metabolized. The area under the concentration-time curve from 0 to infinity [AUC((0-∞))] of plasma radioactivity was approximately 14-fold higher than the sum of the AUC((0-∞)) of remogliflozin etabonate, remogliflozin, and 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-ß-d-glucopyranoside (GSK279782), a pharmacologically active N-dealkylated metabolite. Elimination half-lives of total radioactivity, remogliflozin etabonate, and remogliflozin were 6.57, 0.39, and 1.57 h, respectively. Products of remogliflozin etabonate metabolism are eliminated primarily via renal excretion, with 92.8% of the dose recovered in the urine. Three glucuronide metabolites made up the majority of the radioactivity in plasma and represent 67.1% of the dose in urine, with 5-methyl-1-(1-methylethyl)-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-ß-d-glucopyranosiduronic acid (GSK1997711) representing 47.8% of the dose. In vitro studies demonstrated that remogliflozin etabonate and remogliflozin are Pgp substrates, and that CYP3A4 can form GSK279782 directly from remogliflozin. A ketoconazole clinical drug interaction study, along with the human mass balance findings, confirmed that CYP3A4 contributes less than 50% to remogliflozin metabolism, demonstrating that other enzyme pathways (e.g., P450s, UDP-glucuronosyltransferases, and glucosidases) make significant contributions to the drug's clearance. Overall, these studies support a low clinical drug interaction risk for remogliflozin etabonate due to the availability of multiple biotransformation pathways.


Subject(s)
Glucosides/pharmacokinetics , Ketoconazole/pharmacokinetics , Pyrazoles/pharmacokinetics , Sodium-Glucose Transporter 2 Inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Administration, Oral , Adult , Area Under Curve , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Female , Glucosides/pharmacology , Glucuronides/metabolism , Half-Life , Humans , Ketoconazole/pharmacology , Male , Microsomes, Liver/metabolism , Middle Aged , Pyrazoles/pharmacology , Risk , Sodium-Glucose Transporter 2/metabolism , Young Adult
8.
Clin Pharmacol Drug Dev ; 1(1): 14-23, 2012 Jan.
Article in English | MEDLINE | ID: mdl-27206142

ABSTRACT

LOVAZA (omega-3-acid ethyl esters; eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA]), with diet, lowers very high triglycerides (≥500 mg/dL) in adults. This study evaluated whether an emulsion formulation (LEM) increases the bioavailability of EPA/DHA compared to the reference formulation (RF) in healthy volunteers. Following relative bioavailability assessment, LEM, RF, and placebo were dosed for 2 weeks. Exposure measurements included plasma-free and total fatty acid (EPA/DHA) concentrations and phospholipid and red blood cell (RBC) incorporation. Following single doses, the dose-normalized EPA plasma-corrected AUCs were 14-fold (total) and 12-fold (free) higher and DHA plasma-corrected AUCs were 10-fold (total) and 13-fold (free) higher for LEM compared to RF. EPA and DHA incorporation into phospholipids increased for all active treatments; the increase was dose dependent for EPA. An 8-fold increase over baseline was observed in EPA incorporation for LEM (4-capsule dose) compared to a 4-fold increase for RF 4 g. DHA incorporation increased to a lesser degree, and RBC incorporation also increased. Pharmacodynamic evaluations revealed slight decreases (-8% to -25%) in the mean fasting triglyceride concentrations in all groups, including placebo, compared to baseline. Following a high-fat meal, no consistent treatment-related effect on the triglyceride profiles was observed. Study treatments were safe and tolerated. In conclusion, LEM improves the oral bioavailability of EPA and DHA.

9.
J Obes ; 20112011.
Article in English | MEDLINE | ID: mdl-20847897

ABSTRACT

Evidence of active brown adipose tissue in human adults suggests that this may become a pharmacological target to induce negative energy balance. We have explored whole-body indirect calorimetry to detect the metabolic effects of thermogenic drugs through administration of ephedrine hydrochloride and have assessed ephedrine's merits as a comparator compound in the evaluation of novel thermogenic agents. Volunteers randomly given ephedrine hydrochloride 15 mg QID (n = 8) or placebo (n = 6) were studied at baseline and after 1-2 and 14-15 days of treatment. We demonstrate that overnight or 23-hour, 2% energy expenditure (EE) and 5% fat (FO) or CHO oxidation effects are detectable both acutely and over 14 days. Compared to placebo, ephedrine increased EE and FO rates overnight (EE 63 kJ day 2, EE 105 kJ, FO 190 kJ, day 14), but not over 23 h. We conclude that modest energy expenditure and fat oxidation responses to pharmacological interventions can be confidently detected by calorimetry in small groups. Ephedrine should provide reliable data against which to compare novel thermogenic compounds.

10.
J Clin Pharmacol ; 50(6): 636-46, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20200268

ABSTRACT

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of the sodium-dependent glucose cotransporter-2 in the renal tubule. The pharmacokinetics and pharmacodynamics of sergliflozin were examined during administration of sergliflozin etabonate (500 or 1000 mg) or placebo 3 times daily (tid) for 14 days in healthy overweight or obese human volunteers (n = 18). At the doses tested, sergliflozin showed less than dose-proportional pharmacokinetic characteristics. Mean half-life of the active entity was approximately 2 hours; there was no evidence of drug accumulation. Sergliflozin etabonate produced rapid and sustained suppression of renal glucose reabsorption, resulting in a dose-related glucosuria, and a transient increase in urinary electrolyte and fluid loss; plasma glucose, insulin, and electrolyte levels were unchanged. Sergliflozin etabonate produced a rapid, dose-related reduction in body weight (mean changes of -0.09, -1.55, and -1.74 kg from baseline to day 15 with placebo, sergliflozin etabonate 500 mg, and sergliflozin etabonate 1000 mg, respectively), apparently through increased urinary calorie loss rather than through osmotic diuresis. Sergliflozin etabonate 500 or 1000 mg tid was generally well tolerated; no clinically significant adverse events were identified. Renal function (creatinine clearance) was not affected by sergliflozin etabonate, although urinary microalbumin, N-acetyl-beta-D-glucosaminidase, and beta(2)-microglobulin levels tended to increase.


Subject(s)
Benzhydryl Compounds/pharmacology , Benzhydryl Compounds/pharmacokinetics , Glucosides/pharmacology , Glucosides/pharmacokinetics , Obesity/blood , Obesity/urine , Prodrugs/pharmacology , Prodrugs/pharmacokinetics , Adolescent , Adult , Benzhydryl Compounds/administration & dosage , Benzhydryl Compounds/adverse effects , Blood Glucose/drug effects , Body Weight/drug effects , Dose-Response Relationship, Drug , Drug Monitoring/methods , Female , Glucosides/administration & dosage , Glucosides/adverse effects , Glycosuria/chemically induced , Half-Life , Humans , Insulin/blood , Male , Middle Aged , Overweight/blood , Overweight/urine , Prodrugs/administration & dosage , Prodrugs/adverse effects , Water-Electrolyte Balance/drug effects
11.
J Clin Pharmacol ; 50(6): 623-35, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20056803

ABSTRACT

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5-500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at approximately 30 to 45 minutes postdose (t(max)), and had a plasma elimination half-life (t(1/2)) of approximately 0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose-related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings.


Subject(s)
Benzhydryl Compounds/pharmacology , Benzhydryl Compounds/pharmacokinetics , Diabetes Mellitus, Type 2/drug therapy , Glucosides/pharmacology , Glucosides/pharmacokinetics , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/pharmacokinetics , Prodrugs/pharmacology , Prodrugs/pharmacokinetics , Administration, Oral , Adolescent , Adult , Area Under Curve , Benzhydryl Compounds/administration & dosage , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/urine , Dose-Response Relationship, Drug , Drug Monitoring/methods , Female , Glucose/administration & dosage , Glucose/metabolism , Glucosides/administration & dosage , Glucosides/blood , Glucosides/urine , Glycosuria/metabolism , Humans , Hypoglycemic Agents/administration & dosage , Male , Middle Aged , Prodrugs/administration & dosage , Water-Electrolyte Balance/drug effects
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