Assessment of the Drug Interaction Risk for Remogliflozin Etabonate, a Sodium-Dependent Glucose Cotransporter-2 Inhibitor: Evidence from In Vitro, Human Mass Balance, and Ketoconazole Interaction Studies

Sigafoos, James; Bowers, Gary; Castellino, Stephen; Culp, Amanda; Wagner, David S.; Reese, Melinda J.; Humphreys, Joan E.; Hussey, Elizabeth K.; Semmes, Robin L. O.; Kapur, Anita; Wan, Tao; Dobbins, Robert L.; Polli, Joseph W.

doi:10.1124/dmd.112.047258

Cited by 37 publications

(33 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As such, the SGLT2 inhibitory potency of M4c has not been evaluated; however, existing structure-activity relationships for SGLT2 inhibition suggest that M4c will be inactive as a SGLT2 inhibitor. This hypothesis is consistent with the lack of SGLT2 inhibition by structurally analogous glucuronide derivatives of SGLT2 inhibitors such as dapagliflozin (Forxiga) and remogliflozin (Kasichayanula et al, 2011a,b;Sigafoos et al, 2012). As an unreactive, inactive ether glucuronide, M4c does not raise any particular safety concerns (considering its disproportionate naturehumans .. animals), and in fact this type of glucuronide metabolite is specifically exempted in the Food and Drug Administration Human Metabolites in Safety Testing guidance (http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ ucm079266.pdf).…”

Section: M5asupporting

confidence: 73%

Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects

et al. 2012

View full text Add to dashboard Cite

The disposition of ertugliflozin (PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [ 14 C]-ertugliflozin to healthy human subjects. Mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9% and 50.2%, respectively. The absorption of ertugliflozin in humans was rapid with a T max at ∼1.0 hour. Of the total radioactivity excreted in feces and urine, unchanged ertugliflozin collectively accounted for ∼35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites, M4a, M4b, and M4c (∼39.3% of the dose in urine), of which M4c was the major regioisomer (∼31.7% of the dose). The structure of M4a and M4c were confirmed to be ertugliflozin -4-O-b-and -3-O-b-glucuronide, respectively, via comparison of the HPLC retention time and mass spectra with authentic standards. A minor metabolic fate involved oxidation by cytochrome P450 to yield monohydroxylated metabolites M1 and M3 and des-ethyl ertugliflozin (M2), which accounted for ∼5.2% of the dose in excreta. In plasma, unchanged ertugliflozin and the corresponding 4-O-b-(M4a) and 3-O-b-(M4c) glucuronides were the principal components, which accounted for 49.9, 12.2, and 24.1% of the circulating radioactivity. Overall, these data suggest that ertugliflozin is well absorbed in humans, and eliminated largely via glucuronidation.

show abstract

Section: M5asupporting

confidence: 73%

Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects

et al. 2012

View full text Add to dashboard Cite

show abstract

“…The metabolism of remogliflozin etabonate has been extensively characterized (Figure 1) [25]. This work focused on the potential perpetrator drug interactions that remogliflozin etabonate and its metabolites could have on other therapeutic agents.…”

Section: Background Metabolism Of Remogliflozin Etabonatementioning

confidence: 99%

“…Remogliflozin undergoes further metabolism by CYP enzymes directly yielding GSK279782 and GSK333081, and non-CYP mediated pathways such as glucosidases and UDP-glucuronosyltransferases ultimately yielding glucuronide metabolites. Remogliflozin and GSK279782 are both potent SGLT2 inhibitors (in vitro Ki values ~ 12 nM) [15] and account for the majority of the pharmacological activity in vivo [25]. Of the four non-glucuronide analytes, remogliflozin is the major circulating metabolite, with GSK279782 being 16-22% of remogliflozin exposure.…”

Section: Background Metabolism Of Remogliflozin Etabonatementioning

confidence: 99%

“…Remogliflozin etabonate does not have pharmacological activity and is <2% of the remogliflozin exposure [15]. The final end products of remogliflozin metabolism are three inactive glucuronide conjugates (GSK1997711, GSK1997714, GSK355993), which are eliminated almost exclusively in the urine [25]. GSK1997711 is the largest circulating metabolite, representing 48% of the dose.…”

Section: Background Metabolism Of Remogliflozin Etabonatementioning

confidence: 99%

“…All four compounds had IC 50 values >100 µM for OCT3, demonstrating weak inhibition of this transporter. Finally, the three circulating glucuronide metabolites GSK1997711, GSK1997714 and GSK355993 were tested as OAT1, 3 and 4 inhibitors (0.1 to 300 µM) as they are eliminated in the urine [25]. None of these compounds inhibited the OAT transporters (data not shown).…”

Section: Background Metabolism Of Remogliflozin Etabonatementioning

confidence: 99%

See 2 more Smart Citations

Assessment of Remogliflozin Etabonate, a Sodium-Dependent Glucose Co-Transporter-2 Inhibitor, as a Perpetrator of Clinical Drug Interactions: A Study on Drug Transporters and Metabolic Enzymes

Joseph¹

2012

J Diabetes Metab

View full text Add to dashboard Cite

Type 2 diabetes mellitus is a chronic disease characterized by progressive deterioration of glycemic control and an increased risk of associated complications. Remogliflozin etabonate is the ester prodrug of remogliflozin, a selective sodium-dependent glucose transporter-2 inhibitor that was under development to treat type 2 diabetes. This work investigated the in vitro inhibition of efflux and uptake transporters and cytochrome P450 enzymes by remogliflozin etabonate, remogliflozin and a number of other metabolites. As well, the ability of remogliflozin to induce cytochrome P450 enzymes in human hepatocytes was examined. Remogliflozin etabonate, remogliflozin and GSK279782 (an active pharmacological metabolite of remogliflozin) were inhibitors of organic anion transporting polypeptide-1B1 with IC 50 values of 5.3, 25 and 14 µM, respectively. Remogliflozin etabonate and remogliflozin were inhibitors of organic cation transporter-1 with IC 50 values of 43 and 39 µM, respectively. In contrast, remogliflozin etabonate, remogliflozin, GSK279782, and GSK333081 (a metabolite of remogliflozin) were not inhibitors of P-glycoprotein, a number of other renal transporters, or cytochrome P450 enzymes. Further, three circulating glucuronide metabolites found in human plasma were not inhibitors of cytochrome P450 enzymes or organic anion transporters. Remogliflozin etabonate, but not remogliflozin or GSK279782, activated the pregnane X Receptor in vitro. Further studies demonstrated that remogliflozin (up to 100 µM) did not induce cytochrome P450 3A4 or 1A1 mRNA in human hepatocytes; however a small increase was noted for CYP2B6 mRNA. Combined with pharmacokinetic data from healthy volunteers and diabetic subjects, these in vitro investigations provide a low drug interaction potential for remogliflozin etabonate, remogliflozin and the associated metabolites to be perpetrators of clinical drug interactions. This information has been used to guide the design of clinical studies with remogliflozin etabonate when given with other co-medications.

show abstract

Regional gastrointestinal delivery of remogliflozin etabonate in humans

O’Connor-Semmes

Sandefer²,

Hussey

et al. 2013

Biopharm & Drug Disp

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Assessment of the Drug Interaction Risk for Remogliflozin Etabonate, a Sodium-Dependent Glucose Cotransporter-2 Inhibitor: Evidence from In Vitro, Human Mass Balance, and Ketoconazole Interaction Studies

Cited by 37 publications

References 34 publications

Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects

Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects

Assessment of Remogliflozin Etabonate, a Sodium-Dependent Glucose Co-Transporter-2 Inhibitor, as a Perpetrator of Clinical Drug Interactions: A Study on Drug Transporters and Metabolic Enzymes

Regional gastrointestinal delivery of remogliflozin etabonate in humans

Contact Info

Product

Resources

About