Archives of Diabetes and Endocrine System ISSN 2638-4981 Volume 2, Issue 2, 2019, PP: 13-16 Drug Interactions of sglt2 Inhibitors (Gliflozins) Involving ugt Enzymes Dr. Naina Mohamed Pakkir Maideen PhD,

[email protected] Pharmacologist, Dubai Health Authority, PB No: 4545, Dubai, UAE. *Corresponding Author: Dr. Naina Mohamed Pakkir Maideen PhD, Pharmacologist, Dubai Health Authority, PB No: 4545, Dubai, UAE.

Abstract Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs which are useful in the management of blood sugar of patients with type 2 diabetes, along with diet and exercise. The SGLT2 inhibitors are the substrates of UGT enzymes and SGLT2 inhibitorss uch as Dapagliflozin, Canagliflozin and Ipragliflozin are metabolised by glucuronidation predominantly by UGT1A9 enzyme. In addition, Canagliflozin and Ipragliflozin are also metabolised by UGT2B4. The drugs inhibiting or inducing UGT1A9 and other UGT enzymes are expected to alter the pharmacokinetics of SGLT2 inhibitors. Although the plasma exposure of Dapagliflozin and Canagliflozin are increased slightly by the concomitant use of Mefenamic acid and Probenecid respectively, these interactions were not considered clinically meaningful. Rifampicin and other UGT inducers such as Phenytoin, Phenobarbital and Ritonavir were observed to decrease the plasma levels of Canagliflozin, insignificantly. Based on the results of this review, SGLT2 inhibitors could be coadministered with any medicines without dosage adjustments except Canagliflozin, which needs higher dosage while using along with UGT enzyme inducers. Keywords : Drug interactions; SGLT2 inhibitors; UGT Enzymes; Canagliflozin; Dapagliflozin; Empagliflozin; Ertugliflozin; Ipragliflozin; Luseogliflozin; Tofogliflozin.

Introduction drug by the administration of other drug(s), supplements, Sodium glucose cotransporter 2 (SGLT2) inhibitors smokingModification or alcohol of effects is termed drug of interaction one [3, 4]. are antidiabetic drugs which are useful in the management of blood sugar of patients with type 2 Uridine 5’-diphospho-glucuronosyltransferase (UDP- diabetes, along with diet and exercise. The members of this class of antidiabetic medications approved glucuronosyltransferase, UGT) enzymes are involved by U.S. Food and Drug Administration (FDA) include consistsin Phase of II metabolism UGT1 and UGT2(glucuronidation) families that of furthercertain divideddrugs. Theas subfamilies superfamily of UGT1A, of human UGT2A, UGT and enzymes UGT2B Canagliflozin, Dapagliflozin, Empagliflozin, and and the members of these families include UGT1A1, areErtugliflozin. approved In in addition, Japan [1]. the SGLT2 other inhibitors SGLT2 inhibitors prevent UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, thesuch reabsorption as Ipragliflozin, of glucose Luseogliflozin, and facilitate and Tofogliflozinits excretion UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15 and UGT2B17 [5]. The SGLT2 inhibitors such as through urine by inhibiting Sodium-glucose co- transporter-2 in the proximal convoluted tubule, metabolised by glucuronidation predominantly which results in decrease in blood sugar [2]. Dapagliflozin, Canagliflozin and Ipragliflozin are The probability of drug interactions is higher among diabetic patients since they use number by UGT1A9 enzyme. In addition, Canagliflozin and of comedications to treat their comorbidities. byIpragliflozin UGT1A3, UGT1A8, are also UGT1A9 metabolised and UGT2B7 by UGT2B4. [6]. The other SGLT2 inhibitor, Empagliflozin is metabolised Archives of Diabetes and Endocrine System V2 . I2 . 2019 13 Drug Interactions of sglt2 Inhibitors (Gliflozins) Involving ugt Enzymes The drugs inhibiting or inducing UGT1A9 and other did not result in any alteration in the clearance of Concomitant use of Canagliflozin and Acetaminophen interactions of SGLT2 inhibitors. Acetaminophen [12]. UGT enzymes may play a major role in the drug Mefenamic Acid Warfarin Warfarin is an oral anticoagulant drug and it is used mainly to manage conditions such as Deep vein Mefenamic acid is a Non-steroidal anti-inflammatory drug (NSAID) and it has been identified as a strong theinhibitor concurrent of UGT1A9 use ofenzyme. Mefenamic The plasma acid. However, exposure noof thrombosis (DVT) and Pulmonary embolism (PE) and Dapagliflozin observed to be increased modestly by The pharmacokinetics parameters of Warfarin was to prevent stroke in patients with atrial fibrillation [13]. drugs concomitantly [7]. dosage adjustments are required while using these [14] or Probenecid not affected by the concurrent use of Dapagliflozin DigoxinCanagliflozin [15]. Probenecid is an agent to treat gout and hyperuricemia Digoxin is a cardiac glycoside and its coadministration UGT1A9. Concomitant administration of Probenecid and it is a known inhibitor of UGT enzymes including result in clinically meaningful interaction, in health with Dapagliflozin [14] or Canagliflozin [15],did not participants. whichand Canagliflozin is considered in clinically healthy participantsirrelevant [8]. resulted in slight increase in the plasma exposure of Canagliflozin, Simvastatin Rifampicin Simvastatin is an agent useful to treat dyslipidemia Rifampicin is an anti-mycobacterial antibiotic and it is used in the treatment of tuberculosis and leprosy [9]. and its concomitant use with Dapagliflozin [14] or plasma exposure of Simvastatin and Simvastatin acid, Canagliflozin [16] resulted in slight increase in the UGT1A9 and the coadministration of Rifampicin in healthy participants. However, these interactions Rifampicin is an inducer of many enzymes including with Dapagliflozin lead to slight decrease in plasma wereValsartan not considered clinically significant. exposure of Dapagliflozin. However, the drug was not considered clinically meaningful and no Valsartan is an angiotensin receptor blocker (ARB) interaction between Dapagliflozin and Rifampicin Nevertheless, and it is used to treat hypertension, heart failure dosage adjustments are required [7]. modestly in healthy participants who took Rifampicin Valsartan in healthy participants, lead to slight the plasma exposure of Canagliflozin was decreased and others. Coadministration of Dapagliflozin and increase in the plasma exposure of Valsartan, which is along with Canagliflozin and the monitoring of blood not clinically important [14]. Other UGT Enzyme Inducers sugar may be required [8]. Oral contraceptives The plasma exposure of Oral contraceptives containing enhanced by the coadministration of UGT inducers suchThe as UGT-mediated Phenytoin, Phenobarbital metabolism or of Ritonavir Canagliflozin resulting is slightly by while Ethinyl estradiol and Levonorgestrel was increased [17] d Oral [10]. Canagliflozin [15] Empagliflozin in decreased plasma concentrations of Canagliflozin contraceptives. Hence, the patients taking Canagliflozin along id not affect the pharmacokinetics of Thiazide Diuretics 300mg,with UGT if needed enzyme [11]. inducers are recommended to increase the dose of Canagliflozin from 100mg to Acetaminophen (Paracetamol) with hypertension and edema. Coadministration of Thiazide diuretics help to manage the patients Acetaminophen is an antipyretic and analgesic medication and it is metabolised primarily by UGT1A6 Canagliflozin and Hydrochlorothiazide in healthy nt. changes in pharmacokinetics of either drugs [18]. participants did not produce any clinically significant enzyme14 and by UGT1A9 enzyme with lesser exteArchives of Diabetes and Endocrine System V2 . I2 . 2019 Drug Interactions of sglt2 Inhibitors (Gliflozins) Involving ugt Enzymes Other Oral antidiabetic drugs [2] Dandona P, Chaudhuri A. Sodium‐glucose co‐transporter 2 inhibitors for type 2 diabetes The plasma exposure of Glyburide and Metformin mellitus: An overview for the primary care did not get altered by their co‐administration with hile the pharmacokinetics practice. 2017 May;71(5):e12937. parameters of physician. International journal of clinical andCanagliflozin Sitagliptin [16] were w not altered by the addition of [3] Maideen NM, Balasubramaniam R. Pioglitazone, Metformin, GlimepirideMoreover, Pharmacologically relevant drug interactions of sulfonylurea antidiabetics with common herbs. Dapagliflozin, in healthy subjects [19]. Journal of Herbmed Pharmacology. 2018;7(3). there was no significant interaction observed in antidiabetic drugs such as Metformin, Sitagliptin, [4] study participants taking Ipragliflozin and other oral and in Japanese patients with type 2 diabetes who AmericanMohamed N, Journal Maideen of P. Physiology, Thiazolidinediones Biochemistry and Pioglitazone, Glimepiride, Miglitol or Mitiglinide [20] andtheir Pharmacology. Drug Interactions 2018;8(2):47-54. involving CYP enzymes. tookConclusion Dapagliflozin and Voglibose concomitantly [21]. [5] glucuronosyltransferases and clinical drug-drug The SGLT2 inhibitors are the substrates of UGT interactions.Kiang TK, Pharmacology Ensom MH, &Chang therapeutics. 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Citation: Maideen NM. Drug Interactions of sglt2 Inhibitors (Gliflozins) Involving ugt Enzymes. Archives of Diabetes and Endocrine System. 2019; 2(2): 13-16. Copyright: © 2019 Maideen NM. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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