Severe hypoglycemia caused by a small dose of repaglinide and concurrent use of nilotinib and febuxostat in a patient wi
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CASE REPORT
Severe hypoglycemia caused by a small dose of repaglinide and concurrent use of nilotinib and febuxostat in a patient with type 2 diabetes Hitomi Komatsu1 · Mariko Enomoto1 · Hisashi Shiraishi1 · Yasuyo Morita1 · Daisuke Hashimoto2 · Shuichi Nakayama2 · Shogo Funakoshi2 · Seiki Hirano2 · Yoshio Terada2 · Mitsuhiko Miyamura1 · Shimpei Fujimoto2 Received: 25 February 2020 / Accepted: 25 March 2020 © The Japan Diabetes Society 2020
Abstract Repaglinide, an oral hypoglycemic agent, is a short-acting insulin secretagogue. We describe a case, in which an extremely low dose of repaglinide caused severe hypoglycemia and novel drug interactions are suggested. A 71-year-old man with type 2 diabetes was taken to the hospital due to consciousness disorder caused by severe hypoglycemia. He was taking repaglinide 0.25 mg once in the morning with nilotinib 400 mg/day and febuxostat 20 mg/day. Endogenous insulin secretion was not suppressed even in hypoglycemia. Detection of plasma repaglinide 10 h after administration in this case indicates delayed elimination of the agent, which might be derived from reduced hepatocyte uptake due to inhibitory effects of nilotinib on OATP1B1 and reduced oxidation of the agents by inhibitory effects of nilotinib, mainly on CYP3A4 activities, and of febuxostat on CYP2C8 activities. Repaglinide is eliminated by the liver, and is a short-acting insulin secretagogue with a good safety profile in patients with type 2 diabetes complicated by renal impairment, including elderly patients; however, its delayed elimination due to drug–drug interactions should be noted. Keywords Repaglinide · Nilotinib · Febuxostat · Drug–drug interaction · Hypoglycemia
Introduction Repaglinide, an oral hypoglycemic agent, is a short-acting insulin secretagogue used to reduce postprandial glucose levels in patients with type 2 diabetes. Since repaglinide and its inactive metabolites are eliminated via the biliaryfecal route, it has a favorable safety profile with a low risk of hypoglycemia in patients with impaired renal function. Repaglinide is extensively metabolized by the hepatic cytochrome P450 (CYP) enzyme system mainly by CYP2C8 and CYP3A4 [1], and agents that inhibit these enzymes raise the plasma concentration of repaglinide [2–4]. Therefore, identification of agents which interact with CYP2C8 and * Shimpei Fujimoto fujimoto@kochi‑u.ac.jp 1
Department of Pharmacy, Kochi Medical School Hospital, Nankoku, Japan
Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko‑cho, Nankoku, Kochi 783‑8505, Japan
2
CYP3A4 is important to enable the safe use of repaglinide. A recent nested case–control study suggests that drug interaction between clopidogrel and repaglinide is clinically relevant and could increase the risk for hypoglycemia [5] and that glucuronidation converts clopidogrel to an inhibitor of CYP2C8 [6]. In addition, cases have been reported in which repaglinide caused severe hypoglycemia due to combined use of brotizolam [7], amiodaron
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