Inger Skånberg

Pharmacokinetics of [14C] omeprazole in patients with impaired renal function

Pharmacokinetics of [14C] omeprazole and its metabolites were studied after single intravenous and oral doses of 20 and 40 mg, respectively, to 12 patients with chronic renal insufficiency. Blood samples for determination of total radioactivity, omeprazole, OH‐omeprazole, sulfone, and sulfide were taken for 24 hours. Urine was collected over 96 hours for determination of total radioactivity and during the first 24 hours for additional assay of omeprazole and metabolites. The mean systemic availability was 70%. The mean plasma t1/2 of omeprazole was 0.6 hours. Unchanged omeprazole was not measurable in urine. Derived pharmacokinetic constants of intact omeprazole were within the range of those reported in healthy individuals. The accumulated 24‐hour excretion of radioactive metabolites was related significantly to creatinine clearance. The cumulative excretion of total radioactivity in urine over 96 hours in percent of given dose varied between 25% and 83%.

Pharmacokinetics of [14C]omeprazole in patients with liver cirrhosis

SummaryThe pharmacokinetics of omeprazole and its metabolites following single doses were studied in 8 patients with liver cirrhosis. Each patient participated in 2 experiments in which [14C]omeprazole was administered either intravenously (20mg) or in an oral solution (40mg) in a randomised crossover design. Plasma concentrations of omeprazole and 2 of its identified metabolites, as well as total radioactivity were followed for 24h; urinary excretion was followed for 96h.The mean elimination half-life of omeprazole in the patients with cirrhosis was 2.8h and the mean total plasma clearance was 67 ml/min (4.02 L/h); corresponding values from separate studies in young healthy volunteers were 0.7h and 594 ml/min (35.64 L/h). The mean systemic availability was nearly 100% in the patients with cirrhosis whereas the previously reported value in young volunteers was only 56%. Almost 80% of a given dose was excreted as urinary metabolites in both patients and young volunteers. It is concluded that, as the hepatic clearance of omeprazole was substantially reduced in these patients, the dose of omeprazole needed for a certain degree of acid suppression is lower in patients with liver cirrhosis.

Pharmacokinetic Study of Omeprazole in Elderly Healthy Volunteers

SummaryThe pharmacokinetics of omeprazole and its metabolites were studied in 8 healthy elderly volunteers using [14C]omeprazole. In another 6 healthy elderly volunteers, the pharmacokinetics of omeprazole were studied using unlabelled drug. Each volunteer received single doses of omeprazole intravenously (20mg) and orally (40mg) as solutions in a randomised crossover design. The plasma concentrations and urinary excretion of omeprazole and metabolites were followed for 24 and 96h, respectively.The results indicate that the average metabolic capacity of omeprazole is decreased in the elderly compared with that found in earlier studies of healthy young individuals. This was reflected in an increase in bioavailability from 56 to 76%, a reduction in mean systemic clearance by approximately 50% (0.25 L/min) and a prolongation of the mean elimination half-life from 0.7 to 1.0h compared with the young.Despite these findings, the considerable overlap in these parameters between young and old volunteers, together with data from previous pharmacodynamic studies and the wide therapeutic range of omeprazole, indicate that dosage reductions are not needed in the elderly.

Omeprazole Treatment Does Not Affect the Metabolism of Caffeine

This study was performed to investigate the possible influence of repeated omeprazole dosing on the metabolism of caffeine, which has been shown to reflect the activity of one specific enzyme within the hepatic cytochrome P450 family, P450IA2. Ten healthy, nonsmoking young men participated in this placebo-controlled double-blind trial. Each subject was given omeprazole, 20 mg, every morning for 1 week and placebo every morning for 1 week in random order and separated by a 2-3 week washout period. On the sixth and seventh days of each period urine was collected twice daily, and urinary metabolites of caffeine were determined by high-performance liquid chromatography. The urinary metabolite ratio of three paraxanthine 7-demethylation products relative to a paraxanthine-hydroxylation product corresponds to caffeine clearance and, therefore, to P450IA2 activity. This calculated ratio was 4.8 (95% confidence interval, 3.9-5.6) in the placebo and 4.6 (95% confidence interval, 3.6-5.5) in the omeprazole period. These results show that the metabolism of caffeine was unaltered following omeprazole treatment, indicating that omeprazole treatment has no influence on cytochrome P450IA2 activity in the clinical situation.

Biliary excretion of intravenous [14C] omeprazole in humans.

We have studied the biliary excretion of [14C] omeprazole in humans. The study was performed in eight healthy subjects and the technique used was based on multiple marker dilution principles with doublelumen tubes placed in both the stomach and intestine. The results obtained show a 16% biliary excretion of [14C] omeprazole. These data suggest a minimal “spillover” of omeprazole from the gastric mucosa into the gastric lumen in humans. The results also agree with previous data of the fecal recovery of radiolabeled omeprazole that suggest that the fecal excretion of intravenous omeprazole in humans is entirely accounted for by biliary excretion.

CORRELATION BETWEEN DRUG, LIPID AND CARBOHYDRATE METABOLISM IN THE RAT AFTER CHRONIC BETA-ADRENORECEPTOR ANTAGONIST TREATMENT

Rats were treated for fourteen months with the two beta-receptor blockers propranolol * (non-selective) and metoprolol * (cardio selective). Activities of hepatic and cardiac enzymes, the level of blood-borne substrates representative for different metabolic steps and different parameters representative for drug metabolism were correlated to each other in all fifteen animals. The chosen enzymes represent aerobic and anaerobic breakdown of glucose, anabolism and catabolism of glycogen, the pentosphosphate shunt, β-oxidation of fatty acids, citric acid cycle and the electron transport chain. The following reactions within drug metabolism were studied: epoxide metabolism, O- and N-demethylation, aromatic and aliphatic hydroxylation, kinetic parameters (K S , K m , V max , ΔOD max ) in the metabolism of metoprolol and cyt-P-450 content. Several correlations were found within lipid and carbohydrate metabolism and the parameters within drug metabolism were also correlated to each other. There were very few correlations between drug metabolism and lipid-carbohydrate metabolism. However, glycogen phosphorylase activity in the heart was negatively correlated to several enzymes in drug metabolism, probably through a common hormonal influence. Glutathione-S-epoxide transferase was positively correlated to the liver activity of glycogen phosphorylase, hexokinase and malic enzyme. This result demonstrates the possible role of glycolysis and malic enzyme for the supply of NADPH in epoxide metabolism. To summarize, lipid – carbohydrate metabolism and drug metabolism seems to be functionally interrelated to a very limited extent.