Abstract
Nateglinide and mitiglinide are immediate short-acting insulinotropic agents. Both are administered preprandially to control postprandial hyperglycemia. Glinide drugs are characterized by immediate onset as well as rapid disappearance of effect as compared with sulfonylurea drugs. We examined the rapidity of onset of the therapeutic effect between nateglinide and mitiglinide by pharmacokinetic/pharmacodynamic analysis using the receptor-binding-dissociation model in rats. Nateglinide or mitiglinide was administered orally or intravenously to rats and blood samples were collected at various time-points post administration. The plasma concentrations of the unbound drug forms and the blood glucose were measured. When the simultaneous fitting of oral administration and intravenous administration was performed using the receptor-binding-dissociation model, the measured values exhibited good correspondence with the fitting curve. Moreover, the time-courses of changes of the receptor-binding rate (sulfonylurea receptor) were examined using the parameters (k on: second-order binding association constant to the receptor, Φ: receptor-binding occupancy ratio) obtained from the analysis. The results showed that the binding rate, which is important for glinide drugs in the early phase after administration, was obviously higher for nateglinide than that for mitiglinide from 10 min after oral administration and between 0 and 30 min after intravenous administration. These results suggest a more rapid onset of the therapeutic effect of nateglinide than that of mitiglinide after the drug is distributed into the blood.
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References
Chachin M, Yamada M, Fujita A, Matsuoka T, Matsushita K, Kurachi Y (2003) Nateglinide, a d-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety, specifically inhibits pancreatic beta-cell-type K(ATP) channels. J Pharmacol Exp Ther 304(3):1025–1032
Furuya Y, Ozeki T, Takayanagi R, Yokoyama H, Okuyama K, Yamada Y (2007) Theory based analysis of anti-inflammatory effect of infliximab on Crohn’s disease. Drug Metab Pharmacokinet 22(1):20–25
Giannaccini G, Lupi R, Trincavelli ML, Navalesi R, Betti L, Marchetti P, Lucacchini A, Del Guerra S, Martini C (1998) Characterization of sulfonylurea receptors in isolated human pancreatic islets. J Cell Biochem 71(2):182–188
Holmann RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, Hua TA, Belenkov Y, Boolell M, Buse JB, Buckley BM, Chacra AR, Chiang FT, Charbonnel B, Chow CC, Davies MJ, Deedwania P, Diem P, Einhorn D, Fonseca V, Califf RM et al (2010) Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 362(16):1463–1476
Ikenoue T, Akiyoshi M, Fujitani S, Okazaki K, Kondo N, Maki T (1997a) Hypoglycaemic and insulinotropic effects of a novel oral antidiabetic agent, (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-d-phenylalanine (A-4166). Br J Pharmacol 120(1):137–145
Ikenoue T, Okazaki K, Fujitani S, Tsuchiya Y, Akiyoshi M, Maki T, Kondo N (1997b) Effect of a new hypoglycemic agent, A-4166 [(-)-N-(trans-4-isopropylcyclohexanecarbonyl)-d-phenylalanine], on postprandial blood glucose excursion: comparison with voglibose and glibenclamide. Biol Pharm Bull 20(4):354–359
Katahira H, Ishida H (2005) Effects of mitiglinide in treatment of impaired glucose tolerance. Nippon Rinsho 63(Suppl 2):444–450
Komatsu H, Ohnota H, Koizumi T, Satoh F (1997) A rapid- and short-acting insulinotropic agent KAD-1229. Nippon Rinsho 55:171–179
McLeod JF (2004) Clinical pharmacokinetics of nateglinide: a rapidly-absorbed, short-acting insulinotropic agent. Clin Pharmacokinet 43(2):97–120
Nakajima Y, Yamamoto K, Shimada S, Kotaki H, Sawada Y, Iga T (1996) In vitro-in vivo correlation of pharmacodynamics of felodipine in essential hypertensive patients based on an ion-channel binding model. Biol Pharm Bull 19(8):1097–1099
Ojima K, Ichikawa K, Fujimori Y, Aoyagi I, Yamato T, Tsuji A, Kusama H, Kojima M, Shibata N (2004a) Characterization of hypoglycemic effect of mitiglinide calcium dihydrate (KAD-1229), a novel hypoglycemic agent—comparison with glibenclamide, a sulfonylurea. Jpn Pharmacol Ther 32(2):65–72
Ojima K, Kiyono Y, Kojima M (2004b) Pharmacological and clinical profile of mitiglinide calcium hydrate (Glufast), a new insulinotropic agent with rapid onset. Nippon Yakurigaku Zasshi 124(4):245–255
Shimada S, Nakajima Y, Yamamoto K, Sawada Y, Iga T (1996) Comparative pharmacodynamics of eight calcium channel blocking agents in Japanese essential hypertensive patients. Biol Pharm Bull 19(3):430–437
Sugiura M, Ohno Y, Yamada Y, Suzuki H, Iga T (2004) Pharmacokinetic/pharmacodynamic analysis of neutrophil proliferation induced by rhG-CSF in patients receiving antineoplastic drugs. Yakugaku Zasshi 124(9):599–604
Yamamoto K, Abe M, Katashima M, Yamada Y, Sawada Y, Iga T (1996) Pharmacodynamic analysis of antiplatelet effect of aspirin in the literature—modeling based on inhibition of cyclooxygenase in the platelet and the vessel wall endothelium. Jpn J Hosp Pharm 22(2):133–141
Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, Woodward M, Ninomiya T, Neal B, MacMahon S, Grobbee DE, Kengne AP, Marre M, Heller S (2010) Severe hypoglycemia and risks of vascular events and death. N Engl J Med 363(15):1410–1418
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We appreciate the important contributions of Satoru Kubo and Tomonori Koizumi to these experiments.
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Takanohashi, T., Arisaka, H., Ubukata, K. et al. Comparison of the rapidity of onset of the therapeutic effect between nateglinide and mitiglinide by PK/PD analysis in rats. Eur J Drug Metab Pharmacokinet 37, 9–15 (2012). https://doi.org/10.1007/s13318-011-0068-3
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DOI: https://doi.org/10.1007/s13318-011-0068-3