Effect of Gemfibrozil, Rifampicin, or Probenecid on the Pharmacokinetics of the SGLT2 Inhibitor Empagliflozin in Healthy Volunteers

Macha, Sreeraj; Koenen, Rüdiger; Sennewald, Regina; Schöne, Katja; Hummel, Noemi; Riedmaier, Stephan; Woerle, Hans J.; Salsali, Afshin; Broedl, Uli C.

doi:10.1016/j.clinthera.2014.01.003

Cited by 30 publications

(25 citation statements)

References 22 publications

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“…The previous pharmacokinetic studies confirmed the absence of pharmacokinetic interaction of EG with pioglitazone 8 , hydrochlorothiazide 10 , torasemide 10 , gemfibrozil 15 , rifampicin 15 , probenecid 15 , linagliptin 21 , or sitagliptin 22 . In addition, pharmacokinetic parameters were checked in special populations with heart failure 5 , renal impairment 11, 12 , or hepatic impairment 14 with no need for dose adjustment.…”

Section: Resultssupporting

confidence: 60%

“…The calculated pharmacokinetic parameters were closely related to previous studies conducted in white German subjects using 25 mg EG. The insignificant difference in ANOVA statistical results (Table 2) of the pharmacokinetic evaluation in Egyptians and white German subjects 13, 15, 20, 38 suggests that no dose adjustment should be considered with administration of 25 mg EG to Egyptian population.…”

Section: Resultsmentioning

confidence: 98%

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Pharmacokinetic Evaluation of Empagliflozin in Healthy Egyptian Volunteers Using LC-MS/MS and Comparison with Other Ethnic Populations

Ayoub

Mowaka

Elzanfaly

et al. 2017

Sci Rep

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The present study considered the pharmacokinetic evaluation of empagliflozin after administration to Egyptian volunteers, and the results were compared with other ethnic populations. The FDA recognizes that standard methods of defining racial subgroups are necessary to compare results across pharmacokinetic studies and to assess potential subgroup differences. The design of the study was as an open labeled, randomized, one treatment, one period, single dose pharmacokinetic study. The main pharmacokinetic parameters estimated were Cmax, Tmax, t1/2, elimination rate constant, AUC0-t and AUC0-inf. The insignificant difference in pharmacokinetic parameters between Egyptians and white German subjects suggests that no dose adjustment should be considered with administration of 25 mg empagliflozin to Egyptian population. A new LC-MS/MS method was developed and validated, allowing sensitive estimation of empagliflozin (25–600 ng mL−1) in human plasma using dapagliflozin as an internal standard (IS). The method was applied successfully on the underlying pharmacokinetic study with enhanced sample preparation that involved liquid-liquid extraction. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 449.01 to 371.21 for empagliflozin and m/z 407.00 to 328.81 for dapagliflozin (IS) was employed utilizing negative mode Electro Spray Ionization (ESI). The validated LC-MS/MS method is suitable for further toxicodynamic and bioequivalence studies.

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Section: Resultssupporting

confidence: 60%

Section: Resultsmentioning

confidence: 98%

Pharmacokinetic Evaluation of Empagliflozin in Healthy Egyptian Volunteers Using LC-MS/MS and Comparison with Other Ethnic Populations

Ayoub

Mowaka

Elzanfaly

et al. 2017

Sci Rep

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“…Additionally, the AUC of empagliflozin was not affected by the coadministration with probenecid (OAT3 inhibitor) of verapamil, a P-gp inhibitor (Macha et al, 2013). For other transporters, empagliflozin has been reported to be an OATP1B1/1B3 substrate, and the AUC of empagliflozin increased to 58.5% and 35.2%, respectively, after coadministration with gemfibrozil (OATP1B1/1B3 and OAT3 inhibitor) and rifampicin (OATP1B1/1B3 inhibitor) (Macha et al, 2014). Based on these results, DDIs of luseogliflozin are unlikely to occur through the inhibition of hepatic uptake or renal secretion via these transporters.…”

Section: Discussionmentioning

confidence: 94%

“…Because the urinary excretion is greater than the glomerular filtrated amount, estimated from the plasma unbound AUC of the drug, these drugs are thought to be secreted in the renal tubules. Actually, empagliflozin is an OAT3 substrate, and a clinical DDI study showed that the renal clearance of empagliflozin is decreased by 50% (Macha et al, 2014). In contrast, the urinary excretion of luseogliflozin, dapagliflozin, canagliflozin and ipragliflozin is relatively low, accounting for 1-4.4% of the dose (Astellas, 2016; Devineni & Polidori, 2015;Sasaki et al, 2014;Scheen, 2014) These amounts correspond to approximately half of the estimated glomerular filtrated amount, indicating that the drugs are likely to be reabsorbed predominantly.…”

Section: Discussionmentioning

confidence: 97%

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In vitro evaluation of potential drug interactions mediated by cytochrome P450 and transporters for luseogliflozin, an SGLT2 inhibitor

et al. 2016

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1. We evaluated potential in vitro drug interactions of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, mediated by CYP inhibition, CYP induction and drug transporters using human liver microsomes, primary hepatocytes and recombinant cells-expressing efflux or uptake transporters, respectively. 2. Human CYP inhibition studies indicated that luseogliflozin was a weak inhibitor for CYP2C19 with an IC value of 58.3 μM, whereas it was not an inhibitor of the other eight major isoforms that were tested. The exposure of primary hepatocytes to luseogliflozin for 72 hrs weakly induced CYP3A4 at a concentration of 10 μM, whereas it did not induce CYP1A2 or CYP2B6 at concentrations of 0.1-10 μM. 3. An in vitro transport study suggested that luseogliflozin is a substrate for human P-glycoprotein (P-gp), but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, organic anion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2. Luseogliflozin weakly inhibited OATP1B3 with an IC value of 93.1 μM, but those for other transporters are greater than 100 μM. 4. Based on the therapeutic plasma concentration of the drug, clinically relevant drug interactions are unlikely to occur between luseogliflozin and coadministered drugs mediated by CYPs and/or transporters.

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Effects of sodium‐glucose co‐transporter 2 inhibitors on liver parameters and steatosis: A meta‐analysis of randomized clinical trials

Coelho

Borges‐Canha

Hafe

et al. 2020

Diabetes Metabolism Res

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Aims Non‐alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in Western countries and a common comorbidity with type 2 diabetes (T2D). It lacks effective pharmacotherapy. We aimed to summarize the evidence on the effects of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors on liver structure and function. Materials and methods Meta‐analysis of randomized clinical trials in PubMed, Web of Science and http://ClinicalTrials.gov from their inception to April 2019. Trials evaluating liver function and/or structure and comparing SGLT2 inhibitors with placebo or other oral antidiabetic drugs in patients with T2D were included. Twenty studies (from 3033) were included. A total of 1950 patients with T2D, with or without NAFLD, were treated with SGLT2 inhibitors for at least 8 weeks, and 1900 patients were used as controls. Independent extraction was carried out by two observers. This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‐Analysis. Results SGLT2 inhibitors induced a significant decrease in serum alanine (−7.43U/L, [95%CI −12.14, −2.71], p < 0.01), in aspartate aminotransferases (−2.83U/L, [−4.71, −0.95], p < 0.01), as well as in gamma glutamyl transferase (−8.21U/L, [−9.52, −6.91], p < 0.01), and an increase in total plasma bilirubin (8.19% [0.79, 15.59], p < 0.01), comparing with placebo or other oral antidiabetic drugs. SGLT2 inhibitors treatment was associated with a decrease in liver steatosis (−3.39% [−6.01, −0.77], p < 0.0.1). Conclusions Treatment with SGLT2 inhibitors improves liver structure and function in patients with T2D. This meta‐analysis suggests that SGLT2 inhibitors are a promising pharmacological approach for treatment of NAFLD.

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Effect of Gemfibrozil, Rifampicin, or Probenecid on the Pharmacokinetics of the SGLT2 Inhibitor Empagliflozin in Healthy Volunteers

Cited by 30 publications

References 22 publications

Pharmacokinetic Evaluation of Empagliflozin in Healthy Egyptian Volunteers Using LC-MS/MS and Comparison with Other Ethnic Populations

Pharmacokinetic Evaluation of Empagliflozin in Healthy Egyptian Volunteers Using LC-MS/MS and Comparison with Other Ethnic Populations

In vitro evaluation of potential drug interactions mediated by cytochrome P450 and transporters for luseogliflozin, an SGLT2 inhibitor

Effects of sodium‐glucose co‐transporter 2 inhibitors on liver parameters and steatosis: A meta‐analysis of randomized clinical trials

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