Abstract
Purpose
Gastro-esophageal reflux disease is common in patients with type 2 diabetes. A common treatment is the co-administration of proton-pump inhibitors (PPIs) and metformin. To date, however, the effects of co-administration of PPIs, which inhibit organic cation transporter (OCT) activity, on the action of metformin (a well-known substrate of OCTs) have not been clearly demonstrated.
Methods
This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 20) received metformin (single dose 1,000 mg on day 1 and single dose 750 mg on day 2, with a 12-h interval) co-administered with placebo or with lansoprazole (30 mg). Plasma concentrations of metformin were measured up to 24 h after the second dose. The glucose-lowering effects of metformin were evaluated by the oral glucose tolerance test before and after each single dose of metformin within the 2-day period.
Results
Lansoprazole increased the mean metformin maximum plasma concentration and area under the plasma concentration–time curve from zero to 24 h after the second dosing by 15 and 17 %, respectively (P < 0.05). Moreover, lansoprazole prolonged the metformin elimination half-life from 3.9 to 4.5 h and decreased its renal clearance by 13 % (P < 0.05). However, lansoprazole had no effect on the maximum glucose level and the area under the serum glucose concentration–time curve of metformin.
Conclusions
Collectively, we found a modest pharmacokinetic drug interaction between lansoprazole and metformin, which suggests that the concomitant use of these drugs should be appropriately monitored. Further studies are warranted to assess changes in metformin pharmacokinetics in patients with diabetes receiving long-term lansoprazole therapy.
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References
Kirpichnikov D, McFarlane SI, Sowers JR (2002) Metformin: an update. Ann Intern Med 137(1):25–33
Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR (2000) Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49(12):2063–2069
Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, Koepsell H (1997) Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16(7):871–881
Zhang L, Dresser MJ, Gray AT, Yost SC, Terashita S, Giacomini KM (1997) Cloning and functional expression of a human liver organic cation transporter. Mol Pharmacol 51(6):913–921
Sirtori CR, Franceschini G, Galli-Kienle M, Cighetti G, Galli G, Bondioli A, Conti F (1978) Disposition of metformin (N, N-dimethylbiguanide) in man. Clin Pharmacol Ther 24(6):683–693
Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, Zanger UM, Keppler D, Schwab M, Schaeffeler E (2009) Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology 50(4):1227–1240
Motohashi H, Sakurai Y, Saito H, Masuda S, Urakami Y, Goto M, Fukatsu A, Ogawa O, K-I I (2002) Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 13(4):866–874
Tornio A, Niemi M, Neuvonen PJ, Backman JT (2012) Drug interactions with oral antidiabetic agents: pharmacokinetic mechanisms and clinical implications. Trends Pharmacol Sci 33(6):312–322
Nies AT, Koepsell H, Damme K, Schwab M (2011) Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handb Exp Pharmacol 201:105–167
DeGorter MK, Xia CQ, Yang JJ, Kim RB (2012) Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol 52:249–273
Nies AT, Hofmann U, Resch C, Schaeffeler E, Rius M, Schwab M (2011) Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs). PloS One 6(7):e22163. doi:10.1371/journal.pone.0022163
Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S, Wiley C, Selvin E, Wilson R, Bass EB, Brancati FL (2007) Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Internal Med 147(6):386–399
Bouchoucha M, Uzzan B, Cohen R (2011) Metformin and digestive disorders. Diabetes Metabol 37(2):90–96. doi:10.1016/j.diabet.2010.11.002
Ferguson DD, DeVault KR (2007) Medical management of gastroesophageal reflux disease. Expert Opin Pharmacother 8(1):39–47. doi:10.1517/14656566.8.1.39
Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, Yue L, Lo JC, Burchard EG, Brett CM, Giacomini KM (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117(5):1422–1431. doi:10.1172/JCI30558
Cho SK, Yoon JS, Lee MG, Lee DH, Lim LA, Park K, Park MS, Chung JY (2011) Rifampin enhances the glucose-lowering effect of metformin and increases OCT1 mRNA levels in healthy participants. Clin Pharmacol Ther 89(3):416–421. doi:10.1038/clpt.2010.266
Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41
He YL, Sabo R, Picard F, Wang Y, Herron J, Ligueros-Saylan M, Dole WP (2009) Study of the pharmacokinetic interaction of vildagliptin and metformin in patients with type 2 diabetes. Curr Med Res Opin 25(5):1265–1272
Pentikainen PJ, Neuvonen PJ, Penttila A (1979) Pharmacokinetics of metformin after intravenous and oral administration to man. Eur J Clin Pharmacol 16(3):195–202
Bachmakov I, Glaeser H, Fromm MF, Konig J (2008) Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on organic anion transporting polypeptides and organic cation transporter 1. Diabetes 57(6):1463–1469
Boehm KM, Gunaga S (2010) Cimetidine-induced lactic acidosis and acute pancreatitis. South Med J 103(8):849
Seo JH, Lee DY, Hong CW, Lee IH, Ahn KS, Kang GW (2013) Severe lactic acidosis and acute pancreatitis associated with cimetidine in a patient with type 2 diabetes mellitus taking metformin. Intern Med 52(19):2245–2248
Kimura N, Masuda S, Tanihara Y, Ueo H, Okuda M, Katsura T, Inui K (2005) Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet 20(5):379–386
Kusuhara H, Ito S, Kumagai Y, Jiang M, Shiroshita T, Moriyama Y, Inoue K, Yuasa H, Sugiyama Y (2011) Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. Clin Pharmacol Ther 89(6):837–844
Somogyi A, Stockley C, Keal J, Rolan P, Bochner F (1987) Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol 23(5):545–551
Higgins JW, Bedwell DW, Zamek-Gliszczynski MJ (2012) Ablation of both organic cation transporter (OCT) 1 and OCT2 alters metformin pharmacokinetics but has no effect on tissue drug exposure and pharmacodynamics. Drug Metab Dispos 40(6):1170–1177
Acknowledgments
This work was supported by a grant from the Key Technologies for New Drug Innovation and Development of China (No. 2011ZXJ09202-13; No. 2012BAK25B00) and the National Natural Science Foundation of China (No.81373947; No.81201985). We thank members of the nursing and research staff who participated in the clinical studies.
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Ding, Y., Jia, Y., Song, Y. et al. The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects. Eur J Clin Pharmacol 70, 141–146 (2014). https://doi.org/10.1007/s00228-013-1604-7
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DOI: https://doi.org/10.1007/s00228-013-1604-7