Omeprazole (Page 5 of 9)
12.3 Pharmacokinetics
Absorption
Omeprazole delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules leave the stomach. Absorption is rapid, with peak plasma levels of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30-40% at doses of 20-40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500-600 mL/min.
The bioavailability of omeprazole increases slightly upon repeated administration of omeprazole delayed-release capsules.
Omeprazole delayed-release capsules 40 mg was bioequivalent when administered with and without applesauce. However, Omeprazole delayed-release capsules 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for Omeprazole delayed-release capsules 20 mg. The clinical relevance of this finding is unknown.
Distribution
Protein binding is approximately 95%.
Metabolism
Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system.
Excretion
Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma — the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity.
Combination Therapy with Antimicrobials
Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of omeprazole were increased (Cmax , AUC0-24 , and T1/2 increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin. The observed increases in omeprazole plasma concentration were associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin.
The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.
Table 2
Tissue | Clarithromycin | Clarithromycin + Omeprazole |
Antrum | 10.48 ± 2.01 (n = 5) | 19.96 ± 4.71 (n=5) |
Fundus | 20.81 ± 7.64 (n = 5) | 24.25 ± 6.37 (n= 5) |
Mucus | 4.15 ± 7.74 (n = 4) | 39.29 ± 32.79 (n=4) |
1 mean ± SD (mcg/g)
Special Populations
Geriatric Population
The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers.
Pediatric Use
The pharmacokinetics of omeprazole have been investigated in pediatric patients 2 to 16 years of age:
Table 3
Single or Repeated Oral Dosing /Parameter | Children† ≤ 20 kg 2-5 years | Children† > 20 kg 6-16 years | Adults‡ (mean 76 kg) 23-29 years(n=12) |
10 mg | 20 mg | ||
Single Dosing | |||
Cmax *(ng/mL) | 288 (n=10) | 495 (n=49) | 668 |
AUC*(ng h/mL) | 511 (n=7) | 1140 (n=32) | 1220 |
Repeated Dosing | |||
Cmax * (ng/mL) | 539 (n=4) | 851 (n=32) | 1458 |
AUC *(ng h/mL) | 1179 (n=2) | 2276 (n=23) | 3352 |
Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg.
† Data from single and repeated dose studies
‡ Data from a single and repeated dose study
Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules
Following comparable mg/kg doses of omeprazole, younger children (2 to 5 years of age) have lower AUCs than children 6 to16 years of age or adults; AUCs of the latter two groups did not differ. [See Dosage and Administration (2) ]
Hepatic Impairment
In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared with an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in normals of 0.5-1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500-600 mL/min in normal subjects. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired should be considered.
Renal Impairment
In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m2 , the disposition of omeprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. No dose reduction is necessary in patients with renal impairment.
Asian Population
In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared with Caucasians. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for Asian subjects should be considered.
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