Five chronic hemodialysis patients (1 woman and 4 men, aged, 46–68 yr) were given an oral dose of 10 mg felodipine followed by 0.057 mg [ 3 H ] felodipine IV. After 5 hours, a hemodialysis treatment lasting 4 hours was performed. Blood and dialysate flows were 200 mL/min and 500 mL/min, respectively. Capillary dialyzers with 1.3 m 2 cellulose acetate membrane were used. The pharmacokinetic characteristics and reduction in diastolic BP were similar to those in hypertensive patients with normal renal function and in uremic patients who were not treated with dialysis. There was no measurable removal of felodipine by hemodialysis. Dialyzer clearance of radioactive metabolites was about 10 mL/min, and only 8.9% of the dose was eliminated by the treatment. The half‐life of radioactive metabolites was 10 days (6–14 days) in three patients dialyzed thrice weekly. Since the metabolites are biologically inactive, no adjustment of dose is required in hemodialysis patients .
Abstract: The ulcerogenic effect of five different salts of alprenolol were tested against placebo in a porcine oesophageal test model. The salts with high water solubility, such as the hydrochloride and the fumarate, gave rise to the highest plasma concentrations of alprenolol and evoked serious oesophageal lesions, while the salts with low solubility – the benzoate, maleate and sebacate – had no irritative effect on the oesophagus. The plasma levels of alprenolol were much higher following administration of alprenolol hydrochloride in the oesophagus than after an identical intraduodenal dose of the same salt possibly because of the avoidance of the first‐pass degradation during oesophageal absorption.
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%.
Abstract: The bioavailability, plasma levels and pharmacological effects of 100 mg of metoprolol tartrate administered as an ordinary tablet and as two different slow‐release (SR) preparations were compared in healthy volunteers after single and multiple doses in one series of experiments. In another the urinary excretion of metoprolol and total radioactivity during 72 hours were determined after single doses of 50 mg of metoprolol‐( 3 H) tartrate in solution and in two SR tablets with different dissolution rates. Administration of metoprolol in SR form reduced the peak plasma levels and delayed the time to reach the peak in comparison with the ordinary tablet. The areas under the plasma concentration curves (AUC) after single doses and between two doses in steady state were almost identical for the SR tablets and the ordinary one. Administration of metoprolol in SR form did not significantly influence the urinary recovery of metoprolol (about 3% of the dose) or the fraction of the radioactive dose excreted via the kidney (>97% for each preparation). The elimination half‐life determined from the post‐absorptive phase of the ordinary tablet was 4.0±0.6 hours. The effect on the exercise heart rate and the blood pressure declined at the same constant rate in the post‐absorptive phase and the rate was virtually identical for the different types of tablets. The time for 50% reduction of the maximum effect was about 8 hours. Both of the effect variables were linearly related to the log plasma concentration for the ordinary tablet and the relationships could be described by the same regression line. No significant correlation between the effects and the plasma levels was obtained for the SR tablets. Despite substantial differences between the peak plasma levels of the ordinary tablet and the SR preparations, both types of tablets induced about the same maximum effects on exercise heart rate and systolic blood pressure and only slightly higher effects were recorded at the end of the dosage interval for the SR tablets.
Eighteen patients (14 men and 4 women, aged 36–74 years) treated with metoprolol for a month were included in the study. Twelve had impaired renal function (IRF) with a glomerular fitration rate (GFR) of 7.5–77.1 mL/min and six having normal renal function (NRF) with a GFR of 84.9–113.0 mL/min. Plasma and urine concentrations of felodipine and metabolites, heart rate, and blood pressure were recorded over 24 hours on day 1 after an oral dose of 10 mg felodipine and 0.04 mg 3 H‐felodipine IV and repeated on day 29 during continuous treatment with felodipine, 10 mg bid. The bioavailability of the oral dose on day 1 and day 29 was 13% and 12.5%, respectively. The terminal plasma half‐life (t 1/2 ) on day 29 was 22 hours and systemic clearance was 490 mL/min on day 1 and 434 mL/min on day 29 (NS). There were no differences in these parameters between NRF and IRF. The protein binding determined by equilibrium dialysis in the six patients with the lowest GFR was 99.74% on day 1 and 99.73% on day 29 and did not differ significantly from previously reported values in healthy subjects. The mean supine blood pressure before the acute dose of felodipine was 164/96 mm Hg in the IRF patients and 145/95 mm Hg in the NRF patients. A maximum decrease of 37/22 mm Hg and 32/19 mm Hg, respectively, was seen within 1.5 hours after dose and at 12 hours the reduction was 12/9 and 15/10 mm Hg, respectively, compared to baseline values. At steady state the morning blood pressure before dose was 152/87 mm Hg in the IRF patients and 129/86 mm Hg in the NRF patients. Similar maximum decreases and effects at 12 hours were seen after dose on day 29 as on day 1. Data on the effect on diastolic blood pressure and plasma felodipine concentrations were well fitted to the E max model. The maximum reduction in diastolic blood pressure using this model was 27% and the plasma concentration leading to 50% of the maximum effect was 6.2 nmol/L. In conclusion, renal disease does not affect the pharmacokinetics of felodipine. The pharmacokinetic and pharmacodynamic effects of felodipine are not altered during steady state. The renal excretion of inactive metabolites is reduced in IRF. However, the accumulation of metabolites in the blood does not affect the protein binding or the clearance of felodipine. No dosage adjustment of felodipine seems to be necessary in patients with hypertension and renal impairment.
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