Lack of Clinically Relevant Drug–Drug Interaction Between Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, and Verapamil, Ramipril, or Digoxin in Healthy Volunteers

Macha, Sreeraj; Sennewald, Regina; Rose, Peter W.; Schoene, K; Pinnetti, Sabine; Woerle, Hans J.; Broedl, Uli C.

doi:10.1016/j.clinthera.2013.02.015

Cited by 31 publications

(17 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding other pharmacokinetic characteristics of this drug, a low distribution in the brain(54.4% of plasma radioactivity) and the testes (542.6% of plasma radioactivity) in rats at 1-24 h after dosing (Hasegawa et al, 2015) could be attributed to P-gp transport. Regarding other SGLT2 inhibitors, dapagliflozin (Obermeier et al, 2010), ipragliflozin (Astellas, 2016), tofogliflozin (Sanofi, 2016), canagliflozin (Devineni & Polidori, 2015), and empagliflozin (Macha et al, 2013) are also substrates for P-gp, suggesting a common characteristic of SGLT2 inhibitors. On the other hand, luseogliflozin is not considered to be a substrate for BCRP, which influences the efflux of drugs in the gastrointestinal tract, brain, testes and placenta (van Herwaarden & Schinkel, 2006;Vlaming et al, 2009).…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 97%

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

et al. 2016

View full text Add to dashboard Cite

show abstract

“…DDI studies in healthy volunteers showed no clinically significant interactions between empagliflozin and warfarin [40] , simvastatin [41] , or other cardiovascular compounds (verapamil, ramipril, and digoxin) [42] . The lack of DDIs between verapamil and empagliflozin indicates there is no relevant effect of P-glycoprotein inhibition on the PK of empagliflozin.…”

Section: Empagliflozinmentioning

confidence: 94%

Drug–Drug Interactions with Sodium-Glucose Cotransporters Type 2 (SGLT2) Inhibitors, New Oral Glucose-Lowering Agents for the Management of Type 2 Diabetes Mellitus

Scheen

2014

Clin Pharmacokinet

View full text Add to dashboard Cite

SUMMARYInhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. They are proposed as a novel approach for the management of type 2 diabetes mellitus. They have proven their efficacy in reducing glycated haemoglobin, without inducing hypoglycaemia, as monotherapy or in combination with various other glucose-lowering agents, with the add-on value of promoting some weight loss and lowering arterial blood pressure. As they may be used concomitantly with many other drugs, we review the potential drug-drug interactions regarding the three leaders in the class (dapagliglozin, canagliflozin and empagliflozin). Most of the available studies were performed in healthy volunteers and have assessed the pharmacokinetic interferences with a single administration of the SGLT2 inhibitor. The exposure (assessed by peak plasma concentrations -C max -and area under the concentrationtime curve -AUC -) to each SGLT2 inhibitor tested was not significantly influenced by the concomitant administration of other glucose lowering agents or cardiovascular agents commonly used in patients with type 2 diabetes. Reciprocally, these medications did not influence the pharmacokinetic parameters of dapagliflozin, canagliflozin or empagliflozin.Some modest changes were not considered as clinically relevant. However, drugs which could specifically interfere with the metabolic pathways of SGLT2 inhibitors (rifampin, inhibitors or inducers of uridine diphosphate-glucuronosyltransferase -UGT -) may result in significant changes in the exposure of SGLT2 inhibitors, as shown for dapagliflozin and canagliflozin.Potential drug-drug interactions in patients with type 2 diabetes receiving a chronic treatment with a SGLT2 inhibitor deserve further attention, especially in the numerous individuals treated with several medications or in more fragile patients with hepatic and/or renal impairment.

show abstract

“…18 No dose adjustment of empagliflozin is required when coadministered with ramipril, digoxin or verapamil. 19 Empagliflozin reduces high glucose induced inflammatory and fibrotic markers by blocking glucose transport and did not induce a compensatory increase in SGLT-1/GLUT-2 expression. It attenuates Toll-like receptor-4 expression, nuclear deoxyribonucleic acid binding for nuclear factor kappa B (NF-κB) and activator protein 1 induced collagen IV expression as well as interleukin-6 secretion suggesting a renoprotective effect related to a reduction of glucotoxicity.…”

Section: Empagliflozinmentioning

confidence: 96%

SGLT-2 inhibitors: the glucosuric antidiabetics

Thaddanee¹,

Khilnani²,

Khilnani³

2013

Int J Basic Clin Pharmacol

View full text Add to dashboard Cite

Despite availability of a number of oral antidiabetics, a sizeable population of diabetics remains uncontrolled. Thus there is growing need of new group of drugs for diabetic control. Understanding renal conservation of glucose by efficient reabsorption through sodium glucose cotransporter-2 (SGLT-2) has paved way for development of an entirely new group of drugs, the SGLT-2 inhibitors. These glucosuric antidiabetic agents have shown promise in early clinical studies. Canagliflozin is recently approved for use in diabetes alone or along with other antidiabetics. Other highly selective inhibitors undergoing various stages of clinical developments are dapagliflozin, sergliflozin, remogliflozin, ipragliflozin, empagliflozin, luseogliflozin, tofogliflozin and desoxyrhaponticin. KGA-2727 (pyrazole-O-glucoside) is the first selective SGLT-1 inhibitor undergoing intense preclinical testing. There are safety issues associated with this group like urogenital infections (fungal), weight loss, initial osmotic diuresis and increased incidence of cardiovascular events. The long term safety remains to be established. Despite these limitations, SGLT-2 inhibition offers a unique target for achieving adequate control of diabetes in adults. [Int J Basic Clin Pharmacol 2013; 2(4.000): 347-352

show abstract

Lack of Clinically Relevant Drug–Drug Interaction Between Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, and Verapamil, Ramipril, or Digoxin in Healthy Volunteers

Cited by 31 publications

References 25 publications

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

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

Drug–Drug Interactions with Sodium-Glucose Cotransporters Type 2 (SGLT2) Inhibitors, New Oral Glucose-Lowering Agents for the Management of Type 2 Diabetes Mellitus

SGLT-2 inhibitors: the glucosuric antidiabetics

Contact Info

Product

Resources

About