h3c h3c

hoc n


CYP2C9->M1:CH2OH (active)

glimepiride glimepiride ch3

CYP2C9->M1:CH2OH (active)

Figure 20.13 • Major biotransformations of second-generation sulfonylureas.

exert significant target-level hypoglycemic activity (e.g., tolbutamide) or undoubtedly can, probably plays a relatively insignificant role with respect to in vivo pharmacological activity: because of relatively rapid oxidation to aldehyde and thence to inactive carboxylic acid, as well as conjugation to inactive jS-d-glucuronide, blood and tissue concentrations do not build to sufficient levels. Similarly, because of rapid conversion to glucuronide or sulfate conjugates, which are eliminated mainly in bile, the O-demethylated metabolite of gliquidone (Fig. 20.13) does not contribute substantively to the hypoglycemic activity of this drug.

Repaglinide undergoes extensive biotransformation in humans,24 and this fact primarily accounts for the modest 56% average oral bioavailability of this drug.25 Oxidative biotransformation catalyzed predominantly by CYP3A4 and CYP2C826,27 produces a dicarboxylic acid (M2, see Fig. 20.14) as the major metabolite, reported to account for >65% of an administered dose of [14C]-repaglinide, and to have no hypoglycemic effect.24,28 Subsequent N-dealkyla-tion to the aniline Ml also occurs, and Ml was found at a slightly higher concentration than M2 in urine,24 but most (—90%) of an administered dose is excreted in feces, of which some 72% is M2. On the other hand, the major circulating fraction of an administered dose is repaglinide, which is rapidly cleared from plasma. Direct phase II conjugation to the acyl glucuronide has been reported.

Biotransformation plays the predominant role in the clearance of nateglinide, with isopropyl side chain-centered phase I biotransformation and direct phase II conjugation as key components (Fig. 20.15). Although the p-hydroxyphenyl metabolite has been identified, with respect to phase I biotransformations, only products resulting from the actions of P450s on the isopropyl moiety are reported to be formed in significant quantities in humans. Monohydroxylation of the terminal isopropyl methyls produces two diastereomeric primary alcohols (M2 and M3), both of which are reportedly about a third as pharmacologically active as nateglinide.29 Urinary excretion accounts for about 85% of the elimination of an administered dose, about half of which is M1 and unchanged nateglinide (2:1).30 Following nateglinide administration, Ml is prominent in plasma but reportedly exerts about fivefold or sixfold less potent hypoglycemic activity (intravenous [iv]) than nateglinide. M7 is either formed via direct dehydrogenation of repaglinide, or by elimination of water from Ml, M2, or M3. M7 is also interesting because it exhibits hypoglycemic activity of comparable potency and nature to nateglinide's, although circulating concentrations are almost 10-fold lower than that of nateglinide. Two

Repaglinide Images

acyl p-D-glucuronide H (excreted in bile, cleaved back to repaglinide by microbial glucuronidases)

Figure 20.14 • Important biotransformations of repaglinide. (UDP, undine-3',5'-diphosphate; UDPGA, 3'-phosphoundine-5'-phospho-S-D-glucuronk acid.)

Cyp3a4 Dopamine

Figure 20.15 • Important biotransformations of nateglinide. The abbreviations UDPGA and UDP are defined in the caption to Figure 20.14.

H M6

3-acyloxy rearrangement product

Figure 20.15 • Important biotransformations of nateglinide. The abbreviations UDPGA and UDP are defined in the caption to Figure 20.14.

diastereomeric dihydroxylated metabolites (M11, Ml2, not pictured), together representing —8% of administered dose, may be formed from M7 via epoxidation and spontaneous or epoxide hydrolase-mediated hydrolysis, but detection of the epoxide has yet to be reported, so direct w-1 hydroxylation of M2 and M3, cannot be ruled out as pathways to Mll and Ml 2. Although, apparently, no glucuronides of any of the isopropyl-hydroxylated species have been detected in humans, an acyl jS-d-glucuronopyranoside is produced from the carboxylic acid moiety. Two apparent rearrangement products have also been characterized, in which the acyl group is shifted to the 2'-hydroxyl or 3'-hydroxyl of the sugar (Fig. 20.15), and the three glucuronides in aggregate appear in urine and account for 5% (oral) or 8% (iv) of an administered dose. Because CYP2C9 plays a major role in nateglinide biotransformation, pharmacogenomic variations in PK have been characterized.21,31


Tolbutamide is N-[(butylamino)carbonyl]-4-methylben-zenesulfonamide; or 1-butyl-3-(p-tolylsulfonyl)urea (Orinase, generic). Orinase Diagnostic was the sodium salt, which is freely soluble in water for injection, but this product was discontinued c. 2000.

Acetohexamide is 4-acetyl-N-[(cyclohexylamino)car-bonyl]benzenesulfonamide; or 1-[(p-acetylphenyl)sulfonyl]-3-cyclohexylurea; or 1-(p-acetylbenzenesulfonyl)-3-cyclohe-xylurea (generic). Acetohexamide incorporates the nearly op timal (for potency) cyclohexyl moiety in the "right-hand" side of its molecular structure, but a p-acetyl substituent on the "left-side" benzene ring that decreases lipophilicity and is rapidly biotransformed by reduction to an active metabolite that is cleared relatively rapidly (see preceding discussion) independently of any P450s.

Tolazamide is N-[[(hexahydro-1H-azepin-1-yl)amino] carbonyl]-4-methylbenzenesulfonamide; or 1-(hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl)urea; or 1-(4-methylphe nylsulfonyl)-3-(hexahydro-1H-azepin-1-yl)urea (generic). Tolazamide incorporates a fully saturated azepine moiety that is but weakly basic, with a pKa of — 3.32 The pKa of the sulfonylurea group lies within the typical range; thus, in areas of the duodenum wherein the pH falls within the range of 4 to 5, the uncharged form of the drug is the predominant species, and its lipophilicity lends to rapid absorption by passive diffusion.

Chlorpropamide is 4-chloro-N-[(propylamino)carbo-nyl]benzenesulfonamide; or 1-[(p-chlorophenyl)sulfonyl]-3-propylurea; or 1-(p-chlorobenzenesulfonyl)-3-propylurea (Diabinese, generic). The p-chlorophenyl moiety is quite resistant to P450-mediated hydroxylations; hence, blood levels of the drug are sustained for a markedly long length of time, as aliphatic hydroxylation constitutes most of the clearance, and this happens relatively slowly. Although the w-hydroxyl and (to-1)-hydroxyl metabolites (the latter formed in much greater portion) exert hypoglycemic potencies not much less than does the parent drug, elimination of these by conversion to the corresponding glucuronides occurs more rapidly than hydroxylation of chlorpropamide,33 so blood levels of these metabolites remain low, and thus they probably do not make an appreciable contribution to the hypoglycemic action of this drug in clinical application. Removal of the entire propyl side chain (oxidative A-dealkylation) also occurs to a significant extent (up to 20% of an orally administered dose), creating the inactive metabolite p-chlorobenzenesulfonylurea, about 10% of which degrades to the corresponding benzene-sulfonamide.34

Glipizide is A-[2-[4-[[[(cyclohexylamino)carbonyl] amino]sulfonyl]phenyl]ethyl]-5-methyl-2-pyrazinecarbox-amide; this compound can also be named as the urea—see preceding discussion (Glucotrol, generic). In the United States, combinations are available with metformin (Metaglip, generic; tablets, mg glipizide/mg metformin as hydrochloride: 2.5/250, 2.5/500, 5/500). Extended-release tablets are available (Glucotrol XL, generic). The pyrazine moiety within this structure renders the molecule significantly more hydrophilic than the similar molecule glyburide, albeit also moderately less potent on a dosage as well as target-level basis.

Glyburide (glibenclamide) is 5-chloro-A-[2-[4-[[[(cy-clohexylamino)carbonyl]amino]sulfonyl]phenyl]ethyl]-2-methoxybenzamide; this compound can also be named as the urea—see preceding discussion (Diabeta, Glynase, generic). Some tablet formulations contain micronized drug (formerly Micronase, now only generic). Combinations are available with metformin in the United States (Glucovance, generic; tablets, mg glipizide/mg metformin as hydrochlo-ride: 1.25/250, 2.5/500, 5/500).

Glimepiride is 3-ethyl-2,5-dihydro-4-methyl-A-[2-[4-[[[[(trans-4-methylcyclohexyl)amino]-carbonyl]amino]sul-fonyl]phenyl]ethyl]-2-oxo-1H-pyrrole-1 -carboxamide; this compound can also be named as the urea—see preceding discussion (Amaryl, generic). Combinations are available with rosiglitazone in the United States (Avandaryl tablets; mg glimepiride/mg rosiglitazone as maleate salt: 1/4, 2/4, 4/4, 2/8, 4/8); and with pioglitazone (Duetact tablets; mg glimepiride/ mg pioglitazone as hydrochloride salt: 2/30, 4/30).

Repaglinide is 2-ethoxy-4-[2-[[(15)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoic acid (Prandin); approvals for generics are pending. Combinations are available with metformin in the United States (Prandimet), and the drug may also be coprescribed with one of the thiazolidinediones (typically pioglitazone or rosiglita-zone; see previous discussion). To establish the most clinically valuable dose, the patient is titrated while monitoring blood glucose levels and hemoglobin glycosylation (HbA1c) as an index of longer-term overall control.

Nateglinide (Starlix) is d-Phenylalanine, A-[[trans-4-(1-methylethyl)cyclohexyl]carbonyl]-; or (—)-A-[(trans-4-isopropylcyclohexyl)carbonyl]-d-phenylalanine. In addition to the information given previously and in Table 20.4, it is noteworthy that, although nateglinide is much less potent on a dosage basis than is repaglinide and most of the sul-fonylureas, this drug seems to exhibit unique molecular pharmacodynamics. Nateglinide closes ATP-sensitive K+ channels some threefold more rapidly than repaglinide, and exhibits an off-rate twice as fast as that of glyburide or glimepiride and five times faster than repaglinide.35 These characteristics are reflected by the systemic pharmacodynamics of this drug, translating clinically to improved safety, among other apparent benefits.

Thiazolidinediones (Glitazones)

The thiazolidinedione class of hypoglycemic agents, which are also commonly called glitazones, are represented on the U.S. market by rosiglitazone and pioglitazone (Fig. 20.16). The 2,4-thiazolidinedione (or thiazolidine-2,4-dione) moiety is acidic (Fig. 20.17), with the glitazones exhibiting pKa values near 6.5 to 6.8, and this characteristic is crucial to the target-level pharmacological activity: the negatively charged conjugate base mimics the carboxylate anion of the natural fatty acid ligands (Fig. 20.18).

On the molecular level, the glitazones are thought to mainly exert their hypoglycemic action via binding to the PPARy. The endogenous ligands for PPARs are free fatty acids and eicosanoids (prostaglandins and leukotrienes). The PPARs are nuclear, wherein the glitazone-PPARy complex binds with a retinoid X receptor (RXR). This interaction in turn causes release of corepressor protein by the RXR:HRE complex (HRE, hormone response elements), and upon recruitment of coactivator protein, interaction of the resulting multiprotein complex with DNA promotes transcription. Several biological effects result from the activation of PPARy, but the action of main interest here is sensitization to insulin within key tissues, including the liver, skeletal muscle, and adipose tissue.36,37 Induction of adiponectin synthesis may be a crucial component of this beneficial ef-fect.38,39 Expression levels of PPARy (both subtypes— PPARy1 and PPARy2) are particularly high in adipose tissue, where thiazolidinediones can upregulate adipose triglyceride lipase,40 and exert effects on the expression of several genes suggestive of significant adipose tissue remod-eling.37 Allowing for tissue access differences, the potency of the beneficial effects of these compounds on carbohydrate metabolism for type 2 diabetics parallels potency of agonist effect on PPARy. A relatively recent body of evidence indicates that pancreatic [-cell function is improved as a result of chronic treatment with PPARy agonists.41

Ciglitazone (see Fig. 20.16), a Takeda compound, was the first molecule of this series brought to clinical testing, from which it was withdrawn because of an elevated incidence of cataracts among patients enrolled in longer-term chronic studies. Takeda replaced ciglitazone with pioglitazone, which received Food and Drug Administration (FDA) approval (Actos) in 1999. During the same period, troglitazone was developed by Dai-ichi Sankyo and received FDA approval in January 1997. The trimethylchromanol moiety in troglitazone is the same as in the a-tocopherol form of vitamin E, and troglitazone thereby exhibits significant antioxidant activity. Unfortunately, incidence of hepatotoxicity was substantially higher for troglitazone than either rosiglitazone or pioglita-zone, both of which came on the U.S. market in the summer of 1999. By this time, demarketing of troglitazone worldwide was already occurring, and the FDA issued a formal recall in the following year. A probable basis for troglitazone's hepa-totoxicity, involving one or more reactive metabolites, has recently been elucidated (see succeeding discussion).

Selectivity for PPARy over PPARa or PPARS constitutes a necessary characteristic of molecules intended to therapeutically exploit this mechanism of obtaining insulin-sensitization (although there is rationale for PPARa activity,

Insulin Molecule Ray
Figure 20.16 • Structures of thiazolidinediones used currently or historically, or in late-stage development for treating type 2 diabetes.

and aleglitazar—see structure Fig. 20.18—is a dual PPARy/PPARa agonist currently in clinical trials). Extensive x-ray crystallographic, nuclear magnetic resonance (NMR), and computational chemistry studies provided an understanding that the thiazolidinedione ring not only constitutes a car-boxylate anion isostere in receptor binding, but also that a network of hydrogen bonds to complementary side chain moieties of Ser-289, His-323, Tyr-473, and His-449 accounts for the PPARy selectivity. Moreover, NMR studies suggest that agonist binding selects among a set of interchanging lig-and-binding domain (LBD) conformations (i.e., the LBD region is mobile in the aporeceptor), bestowing a conformation that enables the coactivator recruitment necessary for promoting transcription, over conformations that are not en-abling.42-44 In PPARa, the residue corresponding to His-323 is instead a prohibitively positioned tyrosine, and in PPARS the binding pocket is too narrow to accommodate the thiazol-idinedione ring or substituents a to the acidic moiety, such as occurs in aleglitazar (structure Fig. 20.18). Structure-activity relationships for PPARy ligands have been extensively investigated,11 and many originally empirical observations can now be readily explained based on the knowledge of the binding-pocket structure as discussed previously.

Rosiglitazone and pioglitazone are formulated as their salts (maleate and hydrochloride, respectively). The salts are much more water soluble than the parent acids, conferring rapid dissolution of the drug upon disintegration of a tablet in the stomach. Although the monosubstitution at C5 of the thiazolidinedione ring allows for stereoisomers, interconversion is rapid under physiological conditions, caused by the acidity of the hydrogen at this position, and drugs of this class are therefore sold as racemates. Besides the two products in the list that follows, agents of the thiazolidine class in later stages of clinical development include netoglitazone (RWJ 241947, also known as isaglitazone, MCC 555) and rivoglitazone.45


Rosiglitazone is 5-[4-[2-(n-methyl-n-(2-pyridyl) amino)ethoxy]benzyl]thiazolidine-2,4-dione, and is available as the maleate salt in tablets containing the drug alone (Avandia) or in combination products with metformin (Avandamet) or with glimepiride (Avandaryl). The 2-aminopyridine moiety allows for salt formation; the marketed formulations contain the 1:1 salt with maleic acid, in which the pyridine nitrogen accepts a proton, forming the 2-aminopyridinium species.

Although rosiglitazone is extensively biotransformed— essentially no unchanged drug appears in urine or feces—in humans, only —35% of the administered radioactivity was recovered within 48 hours, and more than a week was required to reach 90% recovery.46 The major routes of biotransformation (Fig. 20.19) are n-demethylation and hydroxylation of the pyridine ring para to the amino nitrogen, with CYP2C8

Canonical Structure Pyridine
Figure 20.17 • Thiazolidinedione nomenclature and numbering, and canonical (resonance) structures representing delocalization of the negative charge in the anionic conjugate base.
Acid Base Partitioning

Figure 20.18 • PPARy ligands of diverse structure, including a natural prostanoid ligand, 15-deoxy-A12'14-PGJ2.

aleglitazar 15-deoxy-A1214-PGJ2

Figure 20.18 • PPARy ligands of diverse structure, including a natural prostanoid ligand, 15-deoxy-A12'14-PGJ2.

TABLE 20.5 Glitazones Marketed in the United States

Acid-Base and Lipid Dosage

Protein Volume of Partitioning Oral Forms and

Drug Binding Distribution Character Biotransformation Bioavailability Elimination Dose Range

Acid-Base and Lipid Dosage

Protein Volume of Partitioning Oral Forms and

Drug Binding Distribution Character Biotransformation Bioavailability Elimination Dose Range



Vss = 17.6 La

pKa 6.5 (HB+)b



t1/2 —4 hr

Tablets: 2 mg,

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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