Info

Log P 0.7 (conj base)'

CYP3A4"

Clss = 7.8 LVhr' ty - 5-7 hr"

5 mg, 6 mg 0.75-20 mg/day

Glimepiride

>99.5%*

Log P 2.9 (free acid)* Log D7 0 1.3*

CYP2C9y,z

<0.5% unchanged drug in urine 37%-52% in urine as metabolites" Clss = 4.3 L/hrf ty -3.4 ± 2 hr"

Tablets: 1 mg, 2 mg, 3 mg, 4 mg, 6 mg, 8 mg 1-8 mg/day

"Half-lives (tu) refer to terminal-phase elimination, unless otherwise noted. fcBrown, K. F.^and Crooks, M. J.: Biochem. Pharmacol. 25(10):1175-1178, 1976. 'Jansson, R„ Bredberg, U„ and Ashton, M.: J. Pharm. Sei. 97(6):2324-2339, 2008. dHanai, T, et al.: Internet Electro. J. Mol. Des. 2(10):702-711, 2003.

ePlumb, R. S„ Potts, W. B. Ill, and Rainville. P. D.: Rapid Commun. Mass Spectrom. 22(14):2139-2152, 2008. 'Kirchheiner, J., Roots, I., and Goldammer, M.: Clin. Pharmacokinet. 44(12):1209-1225, and references therein, 2005. "Jackson J. E„ and Bressler, R.: Drugs 22(3):211-245, 1981. ''Balant, L.: Clin. Pharmacokinet. 6(3):215-241, 1981.

'Galloway, J. A., McMahon, R. E„ Culp, H. W„ et al: Diabetes 16(2):118-127, 1967.

'Llinas, A., Glen, R. C„ and Goodman, J. M.: J. Chem. Inf. Model. 48(7):1289-1303, 2008.

^Lipinski, C. A„ Fiese, E. F., and Korst, R. J.: QSAR 10(2): 109-117, 1991.

'Hughes, L. D„ Palmer, D. S„ and Nigsch, F., et al: J. Chem. Inf. Model. 48(1):220-232, 2008.

'"Taylor, J. A.: Clin. Pharmacol. Ther. 13(5)(Pt. 1):710-718, 1972.

"Crooks, M. J., and Brown, K. F.: J. Pharm. Pharmacol. 26(5):304-311, 1974.

"Thomas, R. C„ et al.: J. Med. Chem. 21 (8):725-732, 1978.

"Kobayashi, K. A., Bauer, L.A., Horn, JR, et al.: Clin. Pharm. 7(3):224-228, 1988.

"Panten, U., Burgfeld, J., Goerke, F., et al.: Biochem. Pharmacol. 38(8):1217-1229, 1989.

'Fuccella, L. M., Tamassia, V., and Valzelli, G.: J. Clin. Pharmacol. New Drugs 13(2):68-75, 1973.

5Balant, L., Fabre, J., and Zahnd, G.R.: Eur. J. Clin. Pharmacol. 8:63-69, 1975.

'Uihlein, M., and Sistovaris, N.: J. Chromatogr. 227:93-101, 1982.

"Zharikova, O. L., Ravindran, S., Nanovskaya, T. N., et al.: Biochem. Pharmacol. 73:2012-2019, 2007. See also references therein. "Rydberg, T„ Wählin-Boll, E„ Melander, A.: J. Chromatogr. 564(1 ):223-233, 1991. wBalant, L., Fabre, J., Loutan, L., et al.: Arzneim. Forsch. 29:162-163, 1979. Ol "Langtry, H. D„ and Balfour, J. A.: Drugs 55(4):563-584, 1998.

N vNiemi, M„ Neuvonen, P. J., and Kivistö, K. T.: Clin. Pharmacol. Ther. 70(5):439-445, 2001. w zWang, R„ Chen, K„ Wen, S. Y„ et al.: Clin. Pharmacol. Ther. 78(1):90-92, 2005.

'Calculated (Accelrys Software, ACD Labs), as reported via SciFinder (Chemical Abstracts Service) accessed Spring 2009.

"From data compiled in Table A-ll-1: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th Edition (McGraw-Hill, 2006).

01GP, alpha 1 acid glycoprotein; ER, extended release; hsa, human serum albumin; NA, not available.

Figure 20.7 • Relationship of first- and second-generation sulfonylurea structures to those of repaglinide and nateglinide, and structural segments engaging the "A" and "B" binding regions at one of the four binding sites (at each SUR1:Kir6.2 interface) of the channel assemblage. Ability to appropriately engage the "A" site confers SUR1 selectivity; after Winkler et al.,4 Vila-Carriles et al.,9 Grell et al.,10 and Sleevi.11

lipophilic (log P —1.8). Moreover, log D peaks near 4.0 between pH 5 and pH 6, even though the amphoteric (doubly charged) form predominates 76:1 over the uncharged species at the pH of log D maximum. Thus, absorption from the gut occurs readily, although there is significant loss caused by first-pass biotransformation (CYP3A4 and CYP2C8; see Table 20.4).

The "structural heritage" of repaglinide is made more obvious by comparison of the structure of meglitinide, a long-known molecule that has not been commercially marketed

Figure 20.7 • Relationship of first- and second-generation sulfonylurea structures to those of repaglinide and nateglinide, and structural segments engaging the "A" and "B" binding regions at one of the four binding sites (at each SUR1:Kir6.2 interface) of the channel assemblage. Ability to appropriately engage the "A" site confers SUR1 selectivity; after Winkler et al.,4 Vila-Carriles et al.,9 Grell et al.,10 and Sleevi.11

as a hypoglycemic agent, to that of glyburide (Fig. 20.10). Moreover, structure-activity relationships reported by Grell et al.10 in conjunction with the molecular biology studies of the receptor by several groups4,9,13 clarify the interactions of these molecules at the interface of the SUR1 protein subunit and the Kir6.2 protein subunits, and provide a basis for selectivity of hypoglycemic sulfonylureas and glinides for SUR1 over the SUR2A-containing channels found in heart and skeletal muscle or the SUR2B-containing channels found in smooth muscle (Figs. 20.2 and 20.7).

Figure 20.8 • Glinide structures, including the prototypical compound meglitinide (see Fig. 20.10).

Kz

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