Structure Of Meglitinide

(30%)fg

fecesaf

t.i.d. (360 mg/day)

information comes from manufacturer's product information unless otherwise indicated.

bScheen, A. J.: Clin. Pharmacokinet. 46(2):93-108, 2007.

cMandic, Z., and Gabelica, V.: J. Pharm. Biomed. Anal. 41(3):866-871, 2006.

dHatorp, V.: Clin. Pharmacokinet. 41(7):471-483, 2002.

evan Heiningen, P. N., Hatorp, V., Kramer Nielsen, K., et al.: Eur. J. Clin. Pharmacol. 55(7):521-525, 1999. ^Weaver, M. L., Orwig, B. A., Rodriguez, L. C., et al.: Drug. Metab. Dispos. 29:415-421, 2001. 9Sabia, H., Sunkara, G., Ligueros-Saylan, M., et al.: Eur. J. Clin. Pharmacol. 60(6):407-412, 2004. a-iGP, alpha glycoprotein; b.i.d., bis in die (twice a day); hsa, human serum albumin; q.i.d.,quater in die (4 times a day); t.i.d., ter in die (3 times a day).

information comes from manufacturer's product information unless otherwise indicated.

bScheen, A. J.: Clin. Pharmacokinet. 46(2):93-108, 2007.

cMandic, Z., and Gabelica, V.: J. Pharm. Biomed. Anal. 41(3):866-871, 2006.

dHatorp, V.: Clin. Pharmacokinet. 41(7):471-483, 2002.

evan Heiningen, P. N., Hatorp, V., Kramer Nielsen, K., et al.: Eur. J. Clin. Pharmacol. 55(7):521-525, 1999. ^Weaver, M. L., Orwig, B. A., Rodriguez, L. C., et al.: Drug. Metab. Dispos. 29:415-421, 2001. 9Sabia, H., Sunkara, G., Ligueros-Saylan, M., et al.: Eur. J. Clin. Pharmacol. 60(6):407-412, 2004. a-iGP, alpha glycoprotein; b.i.d., bis in die (twice a day); hsa, human serum albumin; q.i.d.,quater in die (4 times a day); t.i.d., ter in die (3 times a day).

Recently, evidence indicates that ATP-sensitive K+ channels involved in mediating insulin secretion are found not only on the cell surface, but also at insulin-storage granules,14 and various drugs may differ at least with respect to access to these two sites of action. Also, additional pharmacological targets probably have considerable clinical relevance. For example, gliquidone, glipizide, and nateglinide exhibit peroxisome proliferator-activated receptor-type gamma (PPARy) activity at concentrations reached in tissues under standard pharmacotherapy regimens of these drugs.15 The noteworthiness of this finding will be more apparent to the reader upon completing the section on thia-zolidinediones further on in this chapter. Nateglinide and mitiglinide, but not sulfonylureas, evidently elicit insulin se-

Components Pharmaceutical Chemistry

Figure 20.10 • Comparison of the structure of the prototypical glinide, meglitinide, with that of its "ancestor," glyburide. Comparison to Figure 20.7 will reveal that meglitinide lacks the SUR1 selectivity-bestowing pendant lipophilic group that engages the "A" binding site of the receptor (see Fig. 20.2).

Figure 20.10 • Comparison of the structure of the prototypical glinide, meglitinide, with that of its "ancestor," glyburide. Comparison to Figure 20.7 will reveal that meglitinide lacks the SUR1 selectivity-bestowing pendant lipophilic group that engages the "A" binding site of the receptor (see Fig. 20.2).

cretion in part via a ryanodine-receptor-mediated pathway.16 Still, other molecular targets have been identified for various of these drugs, and these may partly account for the significant pharmacodynamic variations among the sulfonylureas and glinides that have yet to be fully explained. Active metabolites (see succeeding discussion), tissue and serum protein binding, and transporters also undoubtedly play important roles in these variations, some of which are already characterized, and in each such case, the possibility of phar-macogenomic variations among individuals accordingly arises. As an example, repaglinide and nateglinide are substrates of the SLCO1B1--encoded hepatic organic anion uptake transporter (i.e., OATP1B1), and at least one single-nu-cleotide polymorphism significantly alters repaglinide pharmacokinetics (PK)17 and nateglinide PK.18

Regarding biotransformation ("drug metabolism") of the various hypoglycemic sulfonylureas in clinical use, although each drug exhibits a unique fate, common themes are, as is to be expected, associated with structural commonalities among the molecules (Fig. 20.11). Those that include a cyclohexyl ring are hydroxylated on that ring. Just within the past decade, it became clear that for glyburide, not only does hydroxylation occur in humans at each of the possible positions (2, 3, and 4), but with each of the possible stereo-chemical orientations (cis and trans in relative disposition to the attached urea nitrogen); see Figure 20.12.19 Moreover, an ethylene-bridge-hydroxylated metabolite of glyburide (Fig. 20.13), presumably the benzylic hydroxylation product, was identified only within the past decade, and is now known to be a major metabolite in humans.20 Some of these metabolites are known to confer a significant portion of the hypoglycemic effects of this drug, and may account for certain significant pharmacodynamic characteristics of this drug as well as for side effects, especially hypoglycemic episodes. Pharmacologically active metabolites are also known to be important for other sulfonylureas. Notably, the ketone moiety of the p-acetyl substituent on the phenyl ring of acetohexamide is reduced to the corresponding benzylic alcohol (Fig. 20.11), which exhibits a longer pharmacoki-netic half-life than the parent drug, and is approximately

Figure 20.11 • Biotransformations of first-generation sulfonylureas (see also Fig. 20.12).

equiactive with respect to hypoglycemic effect. m-Hydroxylated or (w-l)-hydroxylated metabolites of alkyl chain-containing sulfonylureas are formed and are either known or suspected to contribute to hypoglycemic activity. Those molecules having a p-methylphenyl moiety undergo benzylic hydroxylation. Because this transformation is effected, at least in part, by CYP2C9, pharmacogenomic variations in PK are to be expected.21 For gliclazide, CYP2C19 genetic polymorphism rather than CYP2C9 genetic polymorphism accounts for pharmacogenomic variations in PK.22,23 In each case, though the resulting hydrox-ymethyl metabolite, which is either known to be able to

2-trans

Figure 20.12 • P450-catalyzed cyclohexane ring hydroxylations of glyburide. Evidence suggests that the 2-c/s-hydroxy metabolite (not shown) is also formed, but definitive proof has not been obtained. Also note that some of these metabolites can exist as a pair of enantiomers, concerning which nothing is known.

2-trans

3-trans

Figure 20.12 • P450-catalyzed cyclohexane ring hydroxylations of glyburide. Evidence suggests that the 2-c/s-hydroxy metabolite (not shown) is also formed, but definitive proof has not been obtained. Also note that some of these metabolites can exist as a pair of enantiomers, concerning which nothing is known.

3-c/s: CYP2C8, CYP2C9 3-trans: CYP3A4

h3c h3c

4-trans'. CYP2C8, CYP2C9
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