Sage Journals: Discover world-class research

Abstract

Meglitinides such as repaglinide and nateglinide are useful to treat type 2 diabetes patients who follow a flexible lifestyle. They are short-acting insulin secretagogues and are associated with less risk of hypoglycemia, weight gain and chronic hyperinsulinemia compared with sulfonylureas. Meglitinides are the substrates of cytochrome P450 (CYP) enzymes and organic anion transporting polypeptide 1B1 (OATP1B1 transporter) and the coadministration of the drugs affecting them will result in pharmacokinetic drug interactions. This article focuses on the drug interactions of meglitinides involving CYP enzymes and OATP1B1 transporter. To prevent the risk of hypoglycemic episodes, prescribers and pharmacists must be aware of the adverse drug interactions of meglitinides.

Keywords

drug interactions CYP2C8 CYP2C9 CYP3A4 nateglinide OATP1B1 transporter repaglinide

Introduction

Drug interaction is defined as the interference of effects of one drug by the coadministered drugs, nutrients (food), herbs, alcohol or tobacco smoke.¹ The drug interaction results in either increased or decreased beneficial effects or increased adverse effects. The drug interaction leading to undesirable effects, is termed ‘adverse drug interaction’. Polypharmacy, having liver or kidney disease, or a number of underlying chronic disorders elevate the risk of adverse drug interactions.²

Interacting drugs can alter the pharmacokinetic or pharmacodynamic profile of another. Plasma concentration of one drug is either increased or decreased by altering absorption, distribution, metabolism, or excretion of another drug, and this type of interaction is known as pharmacokinetic drug interactions. The pharmacodynamic interactions are those in which the effect of one drug is altered by the presence of another drug at the same receptor or molecular site.^3–5 Object drug is the one affected by the interaction, and the drug causing the interaction is termed precipitant drug. The absorption, distribution, metabolism, excretion, or actual clinical effect of the object drug is usually modified by the precipitant drug.⁶

The risk of adverse drug interactions is higher in diabetes patients, as they coadminister the medications to manage their comorbidities such as dyslipidemia, hypertension, heart disease, depression, infections, etc., along with their antidiabetic medications. A Brazil study comprised 140 diabetes patients who attended a tertiary care outpatient center, indicated a prevalence of 75% of potential drug–drug interactions, of which 20.7% were major interactions.⁷ And a study from Croatia identified that 80.9% of diabetes patients had at least one potential drug interaction requiring monitoring of therapy.⁸ Most of the antidiabetic drug interactions may result in hypoglycemia-related complications. Severe hypoglycemia is a life-threatening emergency and can result in seizures, coma and death.^9,10

Meglitinides are short-acting insulin secretagogues and they include repaglinide and nateglinide. Repaglinide is a benzoic acid derivative and nateglinide a d-phenylalanine derivative. They are more useful for treating type 2 diabetes mellitus patients having irregular meal times, and act by lowering postprandial glucose primarily. Meglitinides bind to the sulfonylurea receptors (SUR1s) of pancreatic β cells and activate the closure of K_ATP channels [adenosine triphosphate (ATP)-dependent potassium channels] on the β-cell membrane, resulting in depolarization of the β cell and opening of voltage-gated calcium channels. Elevated intracellular calcium concentrations lead to increased fusion of insulin-stored vesicles with the cell membrane, resulting in release of insulin.^11–15 Nateglinide inhibits K_ATP channels faster than repaglinide and it has shorter duration of action and reduced risk of hypoglycemia in comparison with repaglinide.¹² The risk of hypoglycemia, weight gain and chronic hyperinsulinemia is lower with meglitinides compared with sulfonylureas.^14,16

Pharmacokinetic drug interactions of meglitinides

Meglitinides are the substrates of cytochrome P450 (CYP) enzymes and organic anion transporting polypeptide 1B1 (OATP1B1 transporter). Repaglinide is metabolised by CYP2C8 and CYP3A4 enzymes^17,18 while nateglinide is metabolized primarily by CYP2C9 enzyme and by CYP3A4 enzyme to a much lesser extent.^19–21

Organic anion transporting polypeptides (OATPs) are membrane influx transporters and their family consists of 11 members including OATP1B1, OATP1B3 and OATP2B1.²² OATPs are the members of solute-linked carriers (SLCO) superfamily and particularly SLCO21A family; they are ATP-independent polypeptides.^23–25

OATP1B1 transporter found in sinusoidal membrane of hepatocytes aids liver uptake of their substrate drugs.^26–28 The pharmacokinetics of repaglinide is majorly determined by OATP1B1 transporter.²⁹ Nateglinide is also a substrate of OATP1B1 transporter, which determines the hepatic uptake of nateglinide.³⁰

Drug interactions of repaglinide

Drugs inducing or inhibiting CYP enzymes (CYP2C8 and CYP3A4) and OATP1B1 transporter do play an important role in the drug interactions of repaglinide (Figure 1 and Table 1).

Figure 1.

Drug interactions of repaglinide.

Table 1.

Drug interactions of repaglinide.

Interacting drugs	Mechanism of interaction	Comments
Gemfibrozil	Gemfibrozil can increase the plasma concentrations of repaglinide through the inhibition of CYP2C8 enzyme,^31,32 OATP1B1 transporter^33–35 and UGT1A1³⁶	Concomitant use of repaglinide and gemfibrozil should be avoided;³⁸ other fibrates like bezafibrate or fenofibrate may be recommended in patients taking repaglinide³⁹
Clopidogrel	Clopidogrel can inhibit the CYP2C8-mediated metabolism of repaglinide and elevate the risk of hypoglycemia^42,43	Concomitant use of repaglinide and clopidogrel should be avoided; ticagrelor may be used instead of clopidogrel⁴⁴
Cyclosporine	Cyclosporine may increase the plasma concentrations of repaglinide and subsequent hypoglycemia by inhibiting OATP1B1 transporter^26,52 and CYP3A4 enzyme^53,54	Close monitoring of blood glucose is recommended in patients taking cyclosporine and repaglinide⁵⁷
Macrolide antibiotics	Macrolide antibiotics inhibit OATP1B1 transporter⁵⁹ and CYP3A4 enzyme^60,61 and increase the plasma concentrations of repaglinide^62–64	The blood glucose levels should monitored in patients taking repaglinide and macrolide antibiotics together;⁶⁵ azithromycin may be a suitable macrolide for the patients already receiving repaglinide, since it shows least activity against OATP1B1 and CYP3A4⁶⁶
Trimethoprim	Trimethoprim is a potent inhibitor of CYP2C8 enzyme⁶⁷	Monitor the blood glucose levels if used concomitantly
Atorvastatin	Atorvastatin may increase the plasma concentrations of repaglinide through the inhibition of OATP1B1-mediated hepatic uptake⁸⁰ and CYP3A4-mediated metabolism of repaglinide⁸¹	Monitor the blood glucose levels if used concomitantly
Nifedipine	Nifedipine is a moderate competitive inhibitor of CYP3A4 enzyme⁸⁶	Monitor the blood glucose levels if used concomitantly
Rifampicin (Rifampin)	Rifampicin is an inducer of CYP3A4^88,89 and CYP2C8⁹⁰ enzymes and it may decrease the plasma concentrations and therapeutic efficacy of repaglinide^17,91	Monitor the blood glucose levels if used concomitantly
Deferasirox	Deferasirox inhibits CYP3A4 and CYP2C8 enzymes⁹⁴	Monitor the blood glucose levels if used concomitantly⁹⁶

Gemfibrozil

Gemfibrozil is an inhibitor of CYP2C8 enzyme.^31,32 Gemfibrozil and its glucuronide metabolite also inhibit OATP1B1-transporter-mediated hepatic uptake of repaglinide.^33–35 Since repaglinide is the substrate of both CYP2C8 enzyme and OATP1B1 transporter, its concomitant use with gemfibrozil resulted in increased plasma concentrations of repaglinide and subsequent hypoglycemia.^36,37 Gemfibrozil is also found to inhibit Uridine Diphosphate (UDP) glucuronosyltransferase 1A1 (UGT1A1) involving in glucuronidation of repaglinide, resulting in additional elevation of plasma concentrations of repaglinide.³⁶

Hence, the patients on repaglinide should avoid using gemfibrozil.³⁸ Hypertriglyceridemia of the patients taking repaglinide could be treated with either bezafibrate or fenofibrate due to their lack of interaction with repaglinide.³⁹

Clopidogrel

Clopidogrel is a second-generation thienopyridine antiplatelet drug and is a P2Y₁₂ receptor antagonist.⁴⁰ Nowadays, clopidogrel is prescribed most commonly as an antiplatelet drug. The American Diabetes Association (ADA) recommends using clopidogrel as a secondary prevention strategy in diabetes patients with a history of atherosclerotic cardiovascular disease and an intolerance to aspirin therapy.⁴¹

Use of clopidogrel in diabetes patients taking repaglinide may result in elevated plasma concentrations of repaglinide, since glucuronide metabolite of clopidogrel is a strong CYP2C8 inhibitor.^42,43

To avoid hypoglycemia, it is recommended that repaglinide is not coadministered with clopidogrel. Ticagrelor may be a suitable antiplatelet drug to treat diabetes patients taking repaglinide; or else, patients taking clopidogrel may be prescribed nateglinide rather than repaglinide.⁴⁴

Cyclosporine

Cyclosporine is an immunosuppressant medication that decreases the production of inflammatory cytokines by T lymphocytes through the blockade of calcineurin’s phosphatase activity by forming the cyclosporine–cyclophilin complex.⁴⁵

Cyclosporine is less diabetogenic and with less risk of developing post-transplant diabetes mellitus compared with tacrolimus and corticosteroids.⁴⁶ Hence, cyclosporine may be preferred over tacrolimus to treat diabetes patients needing organ transplantation.^47,48 Cyclosporine is identified to reduce the risk of rheumatoid-arthritis-associated atherosclerosis⁴⁹ and hence it may be useful to treat the patients of rheumatoid arthritis with diabetes. Cyclosporine may also be used in treating the patients of systemic lupus erythematosus (SLE) with diabetes, since it decrease the risk of SLE-associated atherosclerosis.⁵⁰ In addition, cyclosporine may be a useful treatment option in patients with resistant Churg-Strauss syndrome (CSS).⁵¹

Cyclosporine is shown to inhibit the OATP1B1 transporter-mediated hepatic uptake of substrates.^26,52 Cyclosporine is also an inhibitor of the CYP3A4 enzyme.^53,54 Hence, cyclosporine may elevate the exposure of repaglinide and the risk of hypoglycemia by inhibiting OATP1B1-transporter-mediated hepatic uptake and CYP3A4-enzyme-mediated metabolism of repaglinide.^55,56 Close monitoring of blood glucose is recommended in patients taking cyclosporine and repaglinide.⁵⁷

Macrolide antibiotics

Macrolide antibiotics include erythromycin, clarithromycin and azithromycin. They are widely used to treat respiratory tract infections and skin and soft tissue infections, primarily.⁵⁸

OATP1B1-mediated hepatic uptake of substrates is inhibited by macrolide antibiotics such as erythromycin, roxithromycin and telithromycin in a concentration-dependent manner.⁵⁹ Macrolide antibiotics such as erythromycin, clarithromycin and roxithromycin can also inhibit intestinal and hepatic CYP3A4 enzyme.^60,61 Concomitant use of repaglinide and clarithromycin or telithromycin resulted in increased plasma concentrations and blood-glucose-lowering effect of repaglinide, which may lead to hypoglycemic risk.^62–64

The blood glucose levels should be monitored in patients taking repaglinide and macrolide antibiotics together.⁶⁵ Azithromycin may be a suitable macrolide for the patients already receiving repaglinide, since it shows least activity against OATP1B1 and CYP3A4.⁶⁶

Trimethoprim

Trimethoprim is a potent inhibitor of CYP2C8 enzyme at clinically relevant concentrations.⁶⁷ In healthy subjects, the plasma concentrations of repaglinide found elevated by trimethoprim are probably due to the inhibition of CYP2C8-mediated metabolism of repaglinide.⁶⁸ The risk of hypoglycemia may be higher in diabetic patients with renal dysfunction and taking repaglinide and trimethoprim concurrently.⁶⁹

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins)

Hydroxymethylglutaryl coenzyme A reductase inhibitors or statins are effective lipid-lowering drugs and they decrease the serum cholesterol by inhibiting hepatic cholesterol biosynthesis, resulting in upregulation of hepatic low-density lipoprotein (LDL) receptors and increased clearance of LDL-cholesterol (LDL-C).⁷⁰ In addition, statins can improve endothelial function and blood flow, enhance the stability of atherosclerotic plaques, decrease oxidative stress and inflammation, inhibit vascular smooth muscle proliferation and platelet aggregation, and reduce vascular inflammation as their cholesterol-independent or ‘pleiotropic’ effects.^71–74

Statins are very much effective in secondary prevention of cardiovascular diseases (CVDs) and decrease the mortality in people with pre-existing CVD.^75,76 Statins are also useful in the primary prevention of cardiovascular diseases (CVD) and reduce the risk of major cardiovascular events like myocardial infarction, stroke, etc. in people without established cardiovascular disease but with cardiovascular risk factors like diabetes, elevated blood pressure, obesity, etc.^77–79

The plasma concentrations of repaglinide might be raised by atorvastatin through the inhibition of OATP1B1-mediated hepatic uptake.⁸⁰ Atorvastatin may also inhibit CYP3A4-mediated metabolism of repaglinide and increase its activity.⁸¹ The bioavailability of oral repaglinide enhanced by fluvastatin might be due to the inhibition of CYP3A4-mediated metabolism of repaglinide.⁸²

Nifedipine

Nifedipine is a dihydropyridine calcium channel blocker and it is useful to treat older patients with systolic hypertension and diabetes.^83,84 Nifedipine found to improve diabetes-associated cognitive impairment as a pleiotropic effect.⁸⁵

Nifedipine is a moderate competitive inhibitor of the CYP3A4 enzyme.⁸⁶ The oral bioavailability of repaglinide may be elevated by the coadministration of nifedipine which can inhibit CYP3A4-mediated metabolism of repaglinide.⁸⁷

Rifampicin (rifampin)

Rifampicin is an antitubercular drug and it is a potent inducer of the CYP3A4 enzyme.^88,89 Rifampicin can also induce the expression of other CYP enzymes, including CYP2C8.⁹⁰ Since rifampicin induces both CYP3A4 and CYP2C8 enzymes, it may decrease the plasma concentrations and therapeutic efficacy of repaglinide.^17,91

Deferasirox

Deferasirox is the most commonly used oral iron chelator and it is useful for the treatment of chronic iron overload resulting from long-term blood transfusions.^92–94 The diabetic patients with β thalassemia may be prescribed deferasirox to treat iron overload.⁹⁵

Deferasirox is a weak inhibitor of both CYP3A4 and CYP2C8 enzymes,⁹⁶ which are involved in the metabolism of repaglinide. Concomitant use of deferasirox and repaglinide warrants careful monitoring of glucose levels.⁹⁷

Drug interactions of nateglinide

Drugs inhibiting or inducing CYP2C9 enzyme and OATP1B1 transporter do play an important role in the drug interactions of nateglinide (Figure 2 and Table 2).

Figure 2.

Drug interactions of nateglinide.

Table 2.

Drug interactions of nateglinide.

Interacting drugs	Mechanism of interaction	Comments
Rifampicin	Rifampicin may decrease plasma concentrations and blood glucose-lowering effect of nateglinide by inducing CYP2C9 enzyme-mediated metabolism of nateglinide¹⁰¹	Monitor the blood glucose levels
Azole antifungals (fluconazole, miconazole)	Fluconazole¹⁰⁶ or miconazole¹⁰⁷ may increase the plasma concentrations of nateglinide through the inhibition of CYP2C9 enzyme-mediated metabolism of nateglinide	Monitor changes in glycemic control

Rifampicin

Rifampicin is primarily used in the treatment of tuberculosis. The diabetic patients with tuberculosis would be prescribed with rifampicin along with other anti-TB drugs.^98–100

Rifampicin may induce CYP2C9 enzyme-mediated oxidative biotransformation of nateglinide resulting in decreased plasma concentrations and blood-glucose-lowering effect of nateglinide. Monitor the blood glucose levels while the initiation and discontinuation of rifampicin in patients taking nateglinide.¹⁰¹

Azole antifungals

The rate of fungal infections is higher in patients with diabetes.^102–104 Fluoconazole is an azole antifungal drug and is recommended in diabetic patients to treat fungal infections, as it is found effective against cutaneous Candidiasis, oropharyngeal Candidiasis (OPC) and vulvovaginal Candidiasis (VVC).¹⁰⁵

The plasma concentrations of nateglinide might be enhanced by the coadministration of fluconazole, which can inhibit the CYP2C9 enzyme-mediated metabolism of nateglinide.¹⁰⁶ CYP2C9 enzyme-mediated metabolism of nateglinide might also be inhibited by miconazole.¹⁰⁷ It is advisable to monitor changes in glycemic control during their concomitant use.

Conclusion

Repaglinide and nateglinide are the substrates of CYP enzymes and OATP1B1 transporter. Repaglinide is metabolized by CYP2C8 and CYP3A4 enzymes and OATP1B1 transporter determines its hepatic uptake. The patients taking repaglinide should avoid using drugs such as gemfibrozil and clopidogrel due to heightened risk of hypoglycemia. Drugs like cyclosporine, macrolide antibiotics, trimethoprim, statins and nifedipine elevate the risk of hypoglycemia in patients taking repaglinide, so blood glucose levels of such patients should be monitored. Concomitant use of repaglinide or nateglinide and rifampicin may result in reduced blood-glucose-lowering effects. To prevent the adverse drug interactions of meglinide antidiabetics, the prescribers and pharmacists must be aware of these effects.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

ORCID iD

Naina Mohamed Pakkir Maideen

References

Baxter

Preston

(eds). Stockley’s drug interactions. London: Pharmaceutical Press, 2010.

Anastasio

Cornell

Menscer

Drug interactions: keeping it straight. Amer Family Phys 1997; 56: 883–888.

Kashuba

Bertino

JS.

Mechanisms of drug interactions I: absorption, metabolism, and excretion. In: Piscitelli

Rodvold

Pai

(eds) Drug interactions in infectious diseases. 2nd ed. Totowa, NJ: Humana Press, 2005, pp.13–39.

D’Arcy

McElnay

Welling

(eds). Mechanisms of drug interactions. Springer Science & Business Media, 2012.

Hussar

DA.

Mechanisms of drug interactions. J Am Pharm Assoc 1969; 9: 208–213.

Ansari

JA.

Drug interaction and pharmacist. J Young Pharm 2010; 2: 326–331.

Trevisan

Silva

Póvoa

et al . Prevalence and clinical significance of potential drug-drug interactions in diabetic patients attended in a tertiary care outpatient center, Brazil. Int J Diabetes Dev Ctries 2016; 36: 283–289.

Samardzic

Bacic-Vrca

Incidence of potential drug–drug interactions with antidiabetic drugs. Die Pharmazie-Int J Pharma Sci 2015; 70: 410–415.

Miller

Phillips

Ziemer

et al . Hypoglycemia in patients with type 2 diabetes mellitus. Arch Intern Med 2001; 161: 1653–1659.

10.

Anderson

Powell

Campbell

et al . Optimal management of type 2 diabetes in patients with increased risk of hypoglycemia. Diabetes Metab Syndr Obes 2014; 7: 85.

11.

Hinnen

DA.

Therapeutic options for the management of postprandial glucose in patients with type 2 diabetes on basal insulin. Clin Diabetes 2015; 33: 175–180.

12.

Stein

Lamos

Davis

SN.

A review of the efficacy and safety of oral antidiabetic drugs. Expert Opin Drug Saf 2013; 12: 153–175.

13.

Quianzon

Cheikh

IE.

History of current non-insulin medications for diabetes mellitus. J Community Hosp Intern Med Perspect 2012; 2: 19081.

14.

Guardado-Mendoza

Prioletta

Jiménez-Ceja

et al . The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus. Arch Med Sci 2013; 9: 936.

15.

Landgraf

Meglitinide analogues in the treatment of type 2 diabetes mellitus. Drugs Aging 2000; 17: 411–425.

16.

Lorenzati

Zucco

Miglietta

et al . Oral hypoglycemic drugs: pathophysiological basis of their mechanism of actionoral hypoglycemic drugs: pathophysiological basis of their mechanism of action. Pharmaceuticals 2010; 3: 3005–3020.

17.

Kajosaari

Laitila

Neuvonen

et al . Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin Pharmacol Toxicol 2005; 97: 249–256.

18.

Bidstrup

Bjørnsdottir

Sidelmann

et al . CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide. British J Clin Pharmacol 2003; 56: 305–314.

19.

Niemi

Backman

Juntti-Patinen

et al . Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide. British J Clin Pharmacol 2005; 60: 208–217.

20.

Kirchheiner

Meineke

Müller

et al . Influence of CYP2C9 and CYP2D6 polymorphisms on the pharmacokinetics of nateglinide in genotyped healthy volunteers. Clin Pharmacokinet 2004; 43: 267–278.

21.

Weaver

Orwig

Rodriguez

et al . Pharmacokinetics and metabolism of nateglinide in humans. Drug Metab Dispos 2001; 29: 415–421.

22.

Kalliokoski

Niemi

Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 2009; 158: 693–705.

23.

Girardin

Membrane transporter proteins: a challenge for CNS drug development. Dialogues Clin Neurosci 2006; 8: 311.

24.

Roth

Obaidat

Hagenbuch

OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol 2012; 165: 1260–1287.

25.

Nigam

SK.

What do drug transporters really do?

Nat Rev Drug Discov 2015; 14: 29.

26.

Shitara

Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions. Drug Metab Pharmacokinet 2011; 26: 220–227.

27.

Gui

Obaidat

Chaguturu

et al . Development of a cell-based high-throughput assay to screen for inhibitors of organic anion transporting polypeptides 1B1 and 1B3. Curr Chem Genomics 2010; 4: 1.

28.

Kalliokoski

Niemi

Impact of OATP transporters on pharmacokinetics. Br J Pharmacol 2009; 158: 693–705.

29.

Niemi

Backman

Kajosaari

et al . Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics. Clin Pharmacol Ther 2005; 77: 468–478.

30.

Takanohashi

Kubo

Arisaka

et al . Contribution of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 to hepatic uptake of nateglinide, and the prediction of drug–drug interactions via these transporters. J Pharm Pharmacol 2012; 64: 199–206.

31.

Honkalammi

Niemi

Neuvonen

et al . Mechanism-based inactivation of CYP2C8 by gemfibrozil occurs rapidly in humans. Clin Pharmacol Ther 2011; 89: 579–586.

32.

Honkalammi

Niemi

Neuvonen

et al . Dose-dependent interaction between gemfibrozil and repaglinide in humans: strong inhibition of CYP2C8 with subtherapeutic gemfibrozil doses. Drug Metab Dispos 2011; 39: 1977–1986.

33.

Kudo

Hisaka

Sugiyama

et al . Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes. Drug Metab Dispos 2012; 41: 362–371.

34.

Varma

Lin

et al . Quantitative rationalization of gemfibrozil drug interactions: consideration of transporters-enzyme interplay and the role of circulating metabolite gemfibrozil 1-O-β-glucuronide. Drug Metab Dispos 2015; 43: 1108–1118.

35.

Karlgren

Ahlin

Bergström

et al . In vitro and in silico strategies to identify OATP1B1 inhibitors and predict clinical drug–drug interactions. Pharm Res 2012; 29: 411–426.

36.

Gan

Chen

Shen

et al . Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism. Br J Clin Pharmacol 2010; 70: 870–880.

37.

Niemi

Backman

Neuvonen

et al . Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003; 46: 347–351.

38.

Grant

Graven

LJ.

Progressing from metformin to sulfonylureas or meglitinides. Workplace Health Saf 2016; 64: 433–439.

39.

Kajosaari

Backman

Neuvonen

et al . Lack of effect of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide. Br J Clin Pharmacol 2004; 58: 390–396.

40.

Jiang

Samant

Lesko

et al . Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet 2015; 54: 147–166.

41.

American Diabetes Association. Standards of medical care in diabetes—2016 abridged for primary care providers. Clin Diab 2016; 34: 3–21.

42.

Kim

Yoshikado

Ieiri

et al . Clarification of the mechanism of clopidogrel-mediated drug-drug interaction in a clinical cassette small-dose study and its prediction based on in vitro information. Drug Metab Dispos 2016; 44: 1622–1632.

43.

Tornio

Filppula

Kailari

et al . Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug–drug interactions. Clin Pharmacol Ther 2014; 96: 498–507.

44.

Wang

Chen

Zhu

et al . Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy. Ther Clin Risk Manag 2015; 11: 449.

45.

Matsuda

Koyasu

Mechanisms of action of cyclosporine. Immunopharmacology 2000; 47: 119–125.

46.

Vincenti

Friman

Scheuermann

et al . Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 2007; 7: 1506–1514.

47.

Dumortier

Bernard

Bouffard

et al . Conversion from tacrolimus to cyclosporine in liver transplanted patients with diabetes mellitus. Liver Transpl 2006; 12: 659–664.

48.

Ghisdal

Bouchta

Broeders

et al . Conversion from tacrolimus to cyclosporine A for new-onset diabetes after transplantation: a single-centre experience in renal transplanted patients and review of the literature. Transpl Int 2008; 21: 146–151.

49.

Kisiel

Kruszewski

Juszkiewicz

et al . Methotrexate, cyclosporine A, and biologics protect against atherosclerosis in rheumatoid arthritis. J Immunol Res 2015; 2015: 1.

50.

Oryoji

Kiyohara

Horiuchi

et al . Reduced carotid intima–media thickness in systemic lupus erythematosus patients treated with cyclosporine A. Mod Rheumatol 2014; 24: 86–92.

51.

McDermott

Powell

Cyclosporin in the treatment of Churg-Strauss syndrome. Ann Rheum Dis 1998; 57: 258–259.

52.

Shitara

Itoh

Sato

et al . Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. J Pharmacol Exp Ther 2003; 304: 610–616.

53.

Gertz

Cartwright

Hobbs

et al . Cyclosporine inhibition of hepatic and intestinal CYP3A4, uptake and efflux transporters: application of PBPK modeling in the assessment of drug-drug interaction potential. Pharm Res 2013; 30: 761–780.

54.

Amundsen

Åsberg

Ohm

et al . Cyclosporine A-and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro. Drug Metab Dispos 2012; 40: 655–661.

55.

Backman

Kajosaari

Niemi

et al . Cyclosporine A increases plasma concentrations and effects of repaglinide. Am J Transplant 2006; 6: 2221–2222.

56.

Kajosaari

Niemi

Neuvonen

et al . Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin Pharmacol Ther 2005; 78: 388–399.

57.

Türk

Witzke

Pharmacological interaction between cyclosporine A and repaglinide. Is it clinically relevant?

Am J Transplant 2006; 6: 2223.

58.

Zuckerman

Qamar

Bono

BR.

Review of macrolides (azithromycin, clarithromycin), ketolids (telithromycin) and glycylcyclines (tigecycline). Med Clin North Am 2011; 95: 761–791.

59.

Seithel

Eberl

Singer

et al . The influence of macrolide antibiotics on the uptake of organic anions and drugs mediated by OATP1B1 and OATP1B3. Drug Metab Dispos 2007; 35: 779–786.

60.

Quinney

Malireddy

Vuppalanchi

et al . Rate of onset of inhibition of gut-wall and hepatic CYP3A by clarithromycin. Eur J Clin Pharmacol 2013; 69: 439–448.

61.

Westphal

JF.

Macrolide–induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol 2000; 50: 285–295.

62.

Niemi

Neuvonen

Kivistö

KT.

The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2001; 70: 58–65.

63.

Plosker

Figgitt

DP.

Repaglinide: a pharmacoeconomic review of its use in type 2 diabetes mellitus. Pharmacoeconomics 2004; 22: 389–411.

64.

Kajosaari

Niemi

Backman

et al . Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide. Clin Pharmacol Ther 2006; 79: 231–242.

65.

Khamaisi

Leitersdorf

Severe hypoglycemia from clarithromycin-repaglinide drug interaction. Pharmacotherapy 2008; 28: 682–684.

66.

Wright

Gomes

Mamdani

et al . The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers. Can Med Assoc J 2011; 183: 303–307.

67.

Wen

Wang

Backman

et al . Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively. Drug Metab Dispos 2002; 30: 631–635.

68.

Niemi

Kajosaari

Neuvonen

et al . The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects. Br J Clin Pharmacol 2004; 57: 441–447.

69.

Roustit

Blondel

Villier

et al . Symptomatic hypoglycemia associated with trimethoprim/sulfamethoxazole and repaglinide in a diabetic patient. Ann Pharmacother 2010; 44: 764–767.

70.

Stancu

Sima

Statins: mechanism of action and effects. J Cell Mol Med 2001; 5: 378–387.

71.

Liao

Laufs

Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005; 45: 89–118.

72.

Marzilli

Pleiotropic effects of statins: evidence for benefits beyond LDL-cholesterol lowering. Am J Cardiovasc Drugs 2010; 10: 3–9.

73.

Kavalipati

Shah

Ramakrishan

et al . Pleiotropic effects of statins. Indian J Endocr Metab 2015; 19: 554–562.

74.

Oesterle

Laufs

Liao

JK.

Pleiotropic effects of statins on the cardiovascular system. Circ Res 2017; 120: 229–243.

75.

Afilalo

Duque

Steele

et al . Statins for secondary prevention in elderly patients: a hierarchical bayesian meta-analysis. J Am Coll Cardiol 2008; 51: 37–45.

76.

Athyros

Papageorgiou

Mercouris

et al . Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. Curr Med Res Opin 2002; 18: 220–228.

77.

Brugts

Yetgin

Hoeks

et al . The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009; 338: b2376.

78.

Taylor

Ward

Moore

et al . Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2011; (1): CD004816.

79.

Ebrahim

Taylor

Brindle

Statins for the primary prevention of cardiovascular disease. BMJ 2014; 348: g280.

80.

Kalliokoski

Backman

Kurkinen

et al . Effects of gemfibrozil and atorvastatin on the pharmacokinetics of repaglinide in relation to SLCO1B1 polymorphism. Clin Pharmacol Ther 2008; 84: 488–496.

81.

Sekhar

Reddy

PJ.

Influence of atorvastatin on the pharmacodynamic and pharmacokinetic activity of repaglinide in rats and rabbits. Mol Cell Biochem 2012; 364: 159–164.

82.

Lee

Choi

Bang

JS.

Effects of fluvastatin on the pharmacokinetics of repaglinide: possible role of CYP3A4 and P-glycoprotein inhibition by fluvastatin. Korean J Physiol Pharmacol 2013; 17: 245–251.

83.

Tuomilehto

Rastenyte

Birkenhäger

et al . Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999; 340: 677–684.

84.

Konzem

Devore

Bauer

DW.

Controlling hypertension in patients with diabetes. Am Fam Physician 2002; 66: 1209–1214.

85.

Tsukuda

Mogi

et al . Diabetes-associated cognitive impairment is improved by a calcium channel blocker, nifedipine. Hypertension 2008; 51: 528–533.

86.

Wrighton

Ring

BJ.

Inhibition of human CYP3A catalyzed 1’-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine. Pharm Res 1994; 11: 921–924.

87.

Choi

DH.

Effects of nifedipine on the pharmacokinetics of repaglinide in rats: possible role of CYP3A4 and P-glycoprotein inhibition by nifedipine. Pharmacol Rep 2013; 65: 1422–1430.

88.

Yamashita

Sasa

Yoshida

et al . Modeling of rifampicin-induced CYP3A4 activation dynamics for the prediction of clinical drug-drug interactions from in vitro data. PLoS One 2013; 8: e70330.

89.

Venkatesan

Pharmacokinetic drug interactions with rifampicin. Clin Pharmacokinet 1992; 22: 47–65.

90.

Rae

Johnson

Lippman

et al . Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther 2001; 299: 849–857.

91.

Niemi

Backman

Neuvonen

et al . Rifampin decreases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2000; 68: 495–500.

92.

Cappellini

Cohen

Piga

et al . A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with β-thalassemia. Blood 2006; 107: 3455–3462.

93.

Piga

Galanello

Forni

et al . Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica 2006; 91: 873–880.

94.

Taher

Cappellini

MD.

Update on the use of deferasirox in the management of iron overload. Ther Clin Risk Manag 2009; 5: 857–868.

95.

Lioudaki

Whyte

Acute cardiac decompensation in a patient with beta-thalassemia and diabetes mellitus following cessation of chelation therapy. Clin Case Rep 2016; 4: 992–996.

96.

Skerjanec

Wang

Maren

et al . Investigation of the pharmacokinetic interactions of deferasirox, a once-daily oral iron chelator, with midazolam, rifampin, and repaglinide in healthy volunteers. J Clin Pharmacol 2010; 50: 205–213.

97.

Tanaka

Clinical pharmacology of deferasirox. Clin Pharmacokinet 2014; 53: 679–694.

98.

Ruslami

Aarnoutse

Alisjahbana

et al . Implications of the global increase of diabetes for tuberculosis control and patient care. Trop Med Int Health 2010; 15: 1289–1299.

99.

Nijland

Ruslami

Stalenhoef

et al . Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin Infect Dis 2006; 43: 848–854.

100.

Chang

Chae

Yun

et al . Effects of type 2 diabetes mellitus on the population pharmacokinetics of rifampin in tuberculosis patients. Tuberculosis 2015; 95: 54–59.

101.

Niemi

Backman

Neuvonen

et al . Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects. Br J Clin Pharmacol 2003; 56: 427–432.

102.

Al-Attas

Amro

SO.

Candidal colonization, strain diversity, and antifungal susceptibility among adult diabetic patients. Ann Saudi Med 2010; 30: 101.

103.

Kumar

Padshetty

Bai

et al . Prevalence of Candida in the oral cavity of diabetic subjects. J Assoc Physicians India 2005; 53: 599–602.

104.

Willis

Coulter

Fulton

et al . Oral candidal carriage and infection in insulin-treated diabetic patients. Diabet Med 1999; 16: 675–679.

105.

Penk

Pittrow

Therapeutic experience with fluconazole in the treatment of fungal infections in diabetic patients. Mycoses 1999; 42: 97–100.

106.

Niemi

Neuvonen

Juntti-Patinen

et al . Effect of fluconazole on the pharmacokinetics and pharmacodynamics of nateglinide. Clin Pharmacol Ther 2003; 74: 25–31.

107.

Takanohashi

Koizumi

Mihara

et al . Prediction of the metabolic interaction of nateglinide with other drugs based on in vitro studies. Drug Metab Pharmacokinet 2007; 22: 409–418.

Drug interactions of meglitinide antidiabetics involving CYP enzymes and OATP1B1 transporter

Abstract

Keywords

Introduction

Pharmacokinetic drug interactions of meglitinides

Drug interactions of repaglinide

Gemfibrozil

Clopidogrel

Cyclosporine

Macrolide antibiotics

Trimethoprim

Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins)

Nifedipine

Rifampicin (rifampin)

Deferasirox

Drug interactions of nateglinide

Rifampicin

Azole antifungals

Conclusion

Footnotes

Funding

Conflict of interest statement

ORCID iD

References