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Kinetics?

Omeprazole

30%-40%

0.5-3.5 hr

95%

0.7 hr

Hydroxy acid sulfide and sulfone

77% urine as metabolites

No

Esomeprazole

64%

1.6 hr

97%

0.9 hr

Hydroxy, desmethyl, sulfone

80% urine as metabolites

No

Lansoprazole

80%

1.7 hr

97%

1.2 hr

Hydroxylated sulfinyl and sulfone

33% urine as metabolites 66% feces as metabolites

Yes

Pantoprazole

77%

2.5 hr

98%

1.2 hr

Demethylation, with subsequent sulfation

71% urine as metabolites 18% feces as metabolites

Yes

Rabeprazole

52%

2-5 hr

96%

1.0 hr

Thioether carboxylic acid, its glucuronide, sulfone, mercapturic acid

90% urine as metabolites

Yes

Source: Facts and Comparisons 4.0, Wolters Kluwer Health, Amsterdam, Netherlands, 2009. *Increases with repeated once-daily dosing.

Source: Facts and Comparisons 4.0, Wolters Kluwer Health, Amsterdam, Netherlands, 2009. *Increases with repeated once-daily dosing.

clude CYP2C19 and CYP3A4, and these catalyze pyridine ring methyl oxidation (CYP2C19: omeprazole, esomepra-zole), benzimidazole ring o-demethylation (CYP2C19: omeprazole and esomeprazole) and sulfoxide oxidation (all PPIs as illustrated in Fig. 23.16) for omeprazole.75,76 The primary metabolite of omeprazole, a racemate, is 5-hydroxy-methylomeprazole, whereas the main metabolite formed from esomeprazole (the ^-isomer) is the sulfone.75,76 Lansoprazole, pantoprazole, and rabeprazole lack the pyridyl 5-methyl group and benzimidazole 5-methoxy group, so they do not undergo these oxidative processes (see structures that follow).75,76

As a result of their metabolic clearance profiles, the PPIs, and especially omeprazole, can interact with other drugs that are also processed by CYP2C19 and CYP3A4 isozymes (Table 23.9). Inhibition of oxidative metabolism by omepra-zole (but not esomeprazole) is responsible for prolonging the clearance of benzodiazepines, phenytoin, and warfarin.66 Lansoprazole decreases theophylline concentration slightly and may decrease the efficacy of oral contraceptives. Pantoprazole and rabeprazole appear to be free of these interactions. Further, the profound and long-lasting inhibition of gastric acid secretion by the PPIs may interfere with the bioavailability of drugs when gastric pH is an important determinant, such as the azole antifungals (e.g., ketoconazole), ampicillin, iron salts, digoxin, and cyanocobalamin (Table 23.9).66

Omeprazole. Omeprazole, 5-methoxy-2-(((4-methoxy-3, 5-dimethyl-2-pyridinyl)methyl) sulfinyl)-1H-benzimidazole (Losec), is a white to off-white crystalline powder with very slight solubility in water. Omeprazole is an amphoteric compound (pyridine N, pKa 4.06; benzimidazole N-H, pKa 0.79), and consistent with the proposed mechanism of action of the substituted benzimidazoles, is acid labile. Hence, the omeprazole product is formulated as delayed-release capsules containing enteric-coated granules.

The absolute bioavailability of orally administered omeprazole is 30% to 40% related to substantial first-pass biotransformation (Table 23.8).66 The drug has a plasma half-life of about 1 hour. Most (77%) of an oral dose of omeprazole is excreted in the urine as metabolites with insignificant antisecretory activity. The primary metabolites of omeprazole are 5-hydroxy omeprazole (CYP2C19) and omeprazole sulfone (CYP3A4). The antisecretory actions of omeprazole persist for 24 to 72 hours, long after the drug has disappeared from plasma, which is consistent with its suggested mechanism of action involving irreversible inhibition of the proton pump.

Pharmaceutical Chemistry Images

Sulfone Metabolite

Figure 23.16 • Metabolic transformations of benzimidazole PPIs.

Sulfone Metabolite

Figure 23.16 • Metabolic transformations of benzimidazole PPIs.

TABLE 23.9 PPI Drug Interactions PPI Drug Interaction Mechanism of Drug Interaction

Azole antifungals

Macrolide antibiotics

Herbals (e.g., ginkgo biloba, St. John's wort Hydantoins (e.g., phenytoin)

Benzodiazepines (e.g., diazepam, triazolam)

Cilostazol, digoxin

Protease inhibitors (e.g., atazanavir, indinavir) Warfarin

Inhibition of PPI (especially omeprazole, esomeprazole) metabolism, resulting in significantly higher drug levels.

PPIs may reduce the GI absorption of azoles by elevating gastric pH and reducing azole solubility in the GI tract

Inhibition of PPI (especially omeprazole, esomeprazole) metabolism, resulting in significantly higher drug levels.

Certain herbals may induce the metabolism of PPIs, especially omeprazole, reducing their plasma concentrations and efficacy.

PPIs, especially omeprazole, may increase serum hydantoin levels. Dose adjustment may be required.

PPIs, especially omeprazole and esomeprazole, may decrease the oxidative metabolism of certain benzodiazepines, thereby reducing their clearance, increasing their half-life and serum levels, and increasing the risk of benzodiazepine-associated adverse effects. Benzodiazepine dosage should be decreased (or dosing interval increased).

PPIs, especially omeprazole, may increase the plasma concentrations of these drugs, thereby increasing their therapeutic effect and adverse effect potential. Consider dosage adjustment of cilostazol.

PPIs may reduce the absorption and plasma levels certain protease inhibitors. Concurrent use of atazanavir and omeprazole is not recommended.

PPIs may increase the hypoprothrombinemic effects of warfarin. The anticoagulant efficacy of warfarin should be monitored when starting or stopping omeprazole.

Source: Facts and Comparisons 4.0, Wolters Kluwer Health, Amsterdam, Netherlands, 2009.

Omeprazole is approved for the treatment of heartburn, GERD, duodenal ulcer, erosive esophagitis, gastric ulcer, and pathological hypersecretory conditions.

Dosage form: Delayed-release tablets (20 mg) and capsules

(20 and 40 mg) Usual adult doses:

• GERD without esophageal lesions: 20 mg/daily for up to 4 weeks

• GERD with erosive esophagitis: 20 mg/daily for 4 to 8 weeks; an additional 4 weeks of treatment may be beneficial

• Duodenal ulcer: 20 mg/day for 4 or more weeks

• Duodenal ulcer associated with H. pylori: Triple therapy with omeprazole 20 mg plus clarithromycin 500 mg plus amoxicillin 1,000 mg, each twice daily for 10 days. If an ulcer is present at the initiation of therapy, continue omeprazole 20 mg for an additional 14 days.

• Erosive esophagitis: 20 mg daily for 4 to 8 weeks; not beyond 12 months

• Gastric ulcer: 40 mg once a day for 4 to 8 weeks

• Pathological hypersecretory conditions: 60 mg daily for as long as indicated; dosages up to 120 mg 3 times per day have been administered.

Esomeprazole Magnesium. Esomeprazole magnesium, s-bis(5-rnethoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-l-yl) magnesium trihydrate (Nexium), is the S-enantiomer of omeprazole. The benzimidazole PPIs contain a chiral sulfur atom that form an enantiomeric pair that is stable and insoluble under standard conditions. The ^-isomer of omeprazole has slightly greater PPI activity, and its intrinsic clearance is approximately three times lower than that of R-omeprazole (15 vs. 43 ^L/min). The lower clearance of S-omeprazole is related to slower metabolic clearance by the CYP2C19 isozyme.66,76 Although R-omeprazole is primarily transformed to the 5-hydroxy metabolite, the ^-isomer is metabolized by o-demethyla-tion and sulfoxidation, which contribute little to intrinsic clearance (Table 23.7).

Dosage forms: Delayed-release capsules (20 or 40 mg), powder for suspension (10, 20, and 40 mg), and powder for injection (20 and 40 mg) Usual adult doses:

• Symptomatic gastroesophageal reflux disease: 20 mg daily usually for 4 weeks

• Erosive esophagitis: 20 or 40 mg daily usually for 4 to 8 weeks

• Duodenal ulcer associated H. pylori eradication: Triple therapy with esomeprazole (40 mg once daily), amoxicillin (1,000 mg twice daily), and clarithromycin (500 mg twice daily), each for 10 days

• Risk reduction of NSAIDs-associated gastric ulcer: 20 or 40 mg daily for up to 6 months

• Pathological hypersecretory conditions, including Zollinger-Ellison syndrome: 40 mg twice daily but doses of up to 240 mg daily have been used

Lansoprazole. Lansoprazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimida-zole (Prevacid), is a white to brownish white, odorless crystalline powder that is practically insoluble in water. Lansoprazole is a weak base (pyridine N, pKa 3.83.) and a weak acid (benzimidazole N-H, pK 0.62). Like other PPIs, lansoprazole is essentially a prodrug that, in the acidic biophase of the parietal cell, forms an active metabolite that irreversibly interacts with the target ATPase of the pump. Lansoprazole must be formulated as encapsulated enteric-coated granules for oral administration to protect the drug from the acidic environment of the stomach.

In the fasting state, about 80% of a dose of lansoprazole (vs. 50% of omeprazole) reaches the systemic circulation, where it is 97% bound to plasma proteins (Table 23.8).66 The drug is metabolized in the liver (sulfone and hydroxy metabolites) and excreted in bile and urine, with a plasma half-life of about 1.5 hours.

Dosage form: Delayed-release and orally disintegrating tablets (15 and 30 mg), delayed-release capsules (5 and 30 mg), delayed-release granules for oral suspension (15 and 30 mg), and a powder for injection (30 mg/vial) Usual adult dose:

• Erosive esophagitis: Initially 30 mg once daily for up to 8 weeks. For adults who do not heal within 8 weeks (5%-10%), an additional 8 weeks of treatment may be given. Then, 15 mg once daily to maintain healing of erosive esophagitis.

• Gastric ulcer: 30 mg once daily for up to 8 weeks

• Gastric associated with NSAIDs: 30 mg once daily for up to 8 weeks to promote healing 15 mg once daily for up to 12 weeks to reduce the risk of NSAID-induced ulcer. Controlled studies did not extend beyond indicated duration.

• Duodenal ulcer: Short-term treatment: 15 mg once daily for 4 weeks for short-term treatment and 15 mg once daily to maintain healing of duodenal ulcers

• Duodenal ulcer associated with h. pylori: Dual therapy with lansoprazole (30 mg) and amoxicillin (1 g) both taken 3 times/day (every 8 hours) for 14 days for patients intolerant or resistant to clarithromycin

• Duodenal ulcer associated with h. pylori: Triple therapy with lansoprazole (30 mg) plus clarithromycin (500 mg) and amoxicillin (1 g), all taken twice daily (every 12 hours) for 10 or 14 days

• Hypersecretory conditions, including Zollinger-Ellison syndrome: Usually an initial dose of 60 mg once daily; dosages up to 90 mg twice daily have been administered

Pantoprazole Sodium. Pantoprazole sodium, racemic-sodium 5-(difluoromethoxy)-2-[[3,4-dimethoxy-2-pyridinyl) methyl]sulfinyl]-1H-benzimidazole sesquihydrate is a white to off-white crystalline powder that is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane. The benzimidazole of this drug has a weakly basic nitrogen (pyridine N, pKa 3.83) and an benzimidazole proton (pKa 0.11), facilitating formulation as a sodium salt. The stability of the compound in aqueous solution is pH dependent; the rate of degradation increases with decreasing pH. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH 5.0 and approximately 220 hours at pH 7.8.

The absorption of pantoprazole is rapid (Cmax of 2.5 ^g/mL, Tmax 2.5 hours) after single or multiple oral 40-mg doses. Pantoprazole is well absorbed (77% bioavail-ability). Administration with food may delay its absorption but does not alter pantoprazole bioavailability. Pantoprazole is distributed mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin. Pantoprazole is extensively metabolized in the liver through the CYP system, including o-demethylation (CYP2C19), with subsequent sulfation. Other metabolic pathways include sulfur oxidation by CYP3A4 (Table 23.8).66 There is no evidence that any of the pantoprazole metabolites have significant pharmacological activity. Approximately 71% of a dose

Chapter 23 # Histamine and Antihistaminic Agents 771

OCHFo

Pantoprazole Sodium of pantoprazole is excreted in the urine, with 18% excreted in the feces through biliary excretion.

Dosage forms: Delayed-release tablets (20 and 40 mg), delayed-release oral suspension (40 mg), and a powder for injection (40 mg) Usual adult dose:

• Erosive esophagitis (maintenance): Usually 40 mg once daily for up to 8 weeks. For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole may be considered. The maintenance dose is 40 mg daily.

• Pathological hypersecretory conditions, including Zollinger-Ellison syndrome: The usual starting dosage is 40 mg twice daily. Adjust dosage regimens to individual patient needs and continue for as long as clinically indicated. Doses of up to 240 mg daily have been administered.

Rabeprazole Sodium. Rabeprazole sodium, 2[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-lH-benzimidazole sodium salt (Aciphex), is a white to slightly yellowish white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform, and ethyl acetate, and insoluble in ether and hexane. Rabeprazole is a weak base (pyridine N, pKa 4.53) and a weak acid (benzimidazole N-H, pKa 0.62), faciliting sodium salt formation.

Rabeprazole sodium is formulated as enteric-coated, delayed-release tablets to allow the drug to pass through the stomach relatively intact. After oral administration of 20-mg peak plasma concentrations (Cmax) occur over a range of 2 to 5 hours (Tmax). Absolute bioavailability for a 20-mg oral tablet of rabeprazole (vs. IV administration) is approximately 52% (Table 23.8).66 The plasma half-life of rabeprazole ranges from 1 to 2 hours. The effects of food on the absorption of rabeprazole have not been evaluated. Rabeprazole is 96% bound to human plasma proteins. Rabeprazole is extensively metabolized in the liver. The thioether and sulfone are the primary metabolites measured in human plasma resulting from CYP3A oxidation. Additionally, desmethyl rabeprazole is formed via the action of CYP2C19. Approximately 90% of the drug is eliminated in the urine, primarily as thioether carboxylic acid and its glucuronide and mercapturic acid metabolites. The remainder of the dose is recovered in the feces. No unchanged rabeprazole is excreted in the urine or feces (Table 23.8).66

Dosage form: Delayed-release tablets (20 mg) Usual adult dose:

• Duodenal ulcers (healing): Usually 20 mg once daily after the morning meal for a period of up to 4 weeks

• Erosive or ulcerative GERD: 20 mg once daily for 4 weeks. If symptoms do not resolve completely after 4 weeks, an additional course of treatment may be considered.

• H. pylori eradication: Triple therapy with rabeprazole (20 mg), amoxicillin (1 g), and clarithromycin (500 mg)

• Treatment of pathological hypersecretory conditions: Usually 60 mg once daily, but doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Some patients may require divided doses. Dosages of up to 100 mg daily and 60 mg twice daily have been administered.

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