The Pharmacokinetics of Omeprazole in Humansmdash;A Study of Single Intravenous and Oral Doses

摘要

The pharamacokinetics of omeprazole, hydroxyomeprazole, omeprazolesulfone, and ldquo;remaining metabolitesrdquo; have been studied in eight young healthy subjects following an acute i.v. and oral dose of 10 and 20 mg of14C-labeled drug, respectively. The oral dose was given as a buffered solution. Two subjects exhibited essentially higher and more sustained plasma levels of omeprazole than the others. This was due to a higher bioavailability, lower clearance, and longert1/2 of omeprazole in these two subjects. Maximum concentration (0.7ndash;4.6 mUmol/L) was reached between 10 and 25 min after oral dosing. The median bioavailability was 39percnt; (25ndash;117percnt;) and the median systemic plasma clearance was 624 ml/min (range of 59ndash;828 ml/min). The correspondingt1/2 for the i.v. dose was 35 min (16ndash;150 min) and 39 min (14ndash;186 min) after oral administration. The drug was rapidly distributed to extravascular sites (meant1/2Lambda;1 = 3.0 pm 0.8 min). MeanVsswas 0.23 pm 0.04 L/kg. Low systemic clearance of omeprazole was associated with a decreased formation rate of hydroxyomepraxole and ldquo;remaining metabolitesrdquo; while omeprazole-sulfone formation seemed to be less affected. However, there was a clear-cut correlation between thet1/2 of omeprazole and of its omeprazolesulfone metabolite, indicating that the elimination of these two compounds is mediated by the same isoenzyme. The mean urinary recovery of the radioactive dose during 96 h was 78.3 pm 2.3 and 75.7 pm 2.6percnt; for the i.v. and oral dose, respectively. Insignificant amounts were due to unchanged drug and omeprazolesulfone. The excretion of hydroxyomeprazole during the first 12 h varied between 4.6 to 15.5percnt; of a given dose. The mean recovery of radioactivity in the feces was 19.3 pm 3.1percnt; of a given i.v. dose and 18.2 pm 2.3percnt; when given orally. It is concluded that omeprazole is mainly eliminated metabolically and that there is a substantial interindividual variation in the rate of formation of primary and secondary metabolites. This variation in omeprazole disposition is probably of limited clinical importance. The half-life, with a maximum of 3 h, is too short to cause accumulation when the drug is administered in a once-daily regimen.