Pharmacokinetics and blood pressure effects of felodipine in elderly hypertensive patients. A comparison with young healthy subjects.

The pharmacokinetics and antihypertensive effects of felodipine, a new dihydropyridine calcium channel blocker, were studied in elderly hypertensive patients, 67 to 79 years of age and in young healthy subjects, 20 to 34 years of age following oral administration of 5 mg twice daily to steady-state. A single intravenous dose of 3H-felodipine (0.04mg) was given together with the oral dose on the study day. Cmax (17 nmol/L), Cmin (5 nmol/L) and AUC (82 nmol/L.h) were 3 times higher in the elderly than in the young subjects. Systemic availability was about 15% in both groups. Plasma clearance (CL) was reduced from 56.1 L/h in the young to 25.4 L/h in the elderly. There was no effect of age on the volume of distribution at steady-state (Vss). Reduced hepatic blood flow and enzyme activity or increased gut wall metabolism are possible reasons for the altered pharmacokinetics in the elderly. Blood pressure was reduced in the elderly from 190/99 to 177/91 mm Hg 12 hours after 5mg felodipine during twice daily dosage. The effect on blood pressure correlated with plasma concentrations of felodipine.

Pharmacokinetics and metabolism of omeprazole in animals and man--an overview.

The pharmacokinetics of omeprazole have been studied to varying extent in the mouse, rat, dog and in man. The drug is rapidly absorbed in all these species. The systemic availability is relatively high in the dog and in man provided the drug is protected from acidic degradation in the stomach. In man the fraction of the oral dose reaching the systemic circulation was found to increase from an average of 40.3 to 58.2% when the dose was raised from 10 to 40 mg, suggesting some dose-dependency in this parameter. The drug distributes rapidly to extra-vascular sites. The volume of distribution, V beta, in man is comparable to the volume of the extracellular water. The penetration into the red cells is low, the ratio between the concentration in whole blood and in plasma being about 0.6. Omeprazole is bound to about 95% to proteins in human plasma. The binding is lower in the dog and rat (90 and 87%, respectively). Omeprazole is eliminated almost completely by metabolism and no unchanged drug has been recovered in the urine in the species studied. Two metabolites, characterised as the sulfone and sulfide of omeprazole, have been identified and quantified in human plasma. The mean elimination half-life in man and in the dog is about 1 hour, whereas half-lives in the range of 5 to 15 minutes have been recorded in the mouse. In two studies in man, the mean total body clearance was 880 and 1097 ml X min-1, indicating that omeprazole belongs to the group of high clearance drugs. In the dog, too, the drug appears to be rapidly cleared from the blood, the mean total body clearance being about 10.5 ml X min-1 X kg-1. In the rat and dog, 20 to 30% of an i.v. or oral dose of omeprazole is excreted as metabolites in the urine and the remaining fraction is recovered in the faeces within three days after the administration. In man, the excretion of radioactivity via the kidneys is much more efficient and the recoveries in the excreta are approximately the reverse of those in the rat and dog. In vitro studies with rat liver microsome preparations suggest that omeprazole and cimetidine inhibit cytochrome P-450-mediated metabolic reactions to about the same extent in equimolar concentrations. However, since the molar daily dose of cimetidine will be 25 to 50 times higher than that of omeprazole, the latter might have less influence on the mixed function oxidase system than cimetidine.(ABSTRACT TRUNCATED AT 400 WORDS)

Determination of four carboxylic acid metabolites of felodipine in plasma by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatography method with ultraviolet detection at 220 nm was developed to determine four carboxylic acid metabolites in plasma following therapeutic doses of the calcium antagonist felodipine. After the addition of an internal standard the analytes were isolated by liquid-liquid and solid-phase extraction. The metabolites were applied to a C2 cartridge in their free acid form, but they were transformed and retained as ion pairs with tetrabutylammonium during a wash with phosphate buffer (pH 7), prior to automated elution and injection by the Varian AASP system onto the analytical C18 column. Using a sample volume of 1 ml of plasma, the lower limit of determination for the metabolites was about 20 nmol/l. The influence of the pH of the mobile phase on the retention time of the metabolites and the structural requirements for the internal standard were studied. The method was applied to plasma samples from four dogs collected after an oral dose of felodipine. The plasma concentration-time profiles of the metabolites gave useful information about the mechanisms by which they were formed and eliminated.

Absorption of beta-adrenoceptor antagonists to Amberlite resin.

The adsorption of beta-adrenoceptor blockers and the partial beta-adrenoceptor agonist prenalterol was studied in an in vitro haemoperfusion (HP) model. Metoprolol, alprenolol, propranolol and prenalterol adsorb well from the blood to the resin with extraction ratios nearing 1.0. Extraction ratio for practolol was 0.68 and for atenolol 0.49. Protein binding has little effect on the degree of adsorption, which is more dependent on water solubility.

Effects of biliary excretion on the disposition of felodipine and metabolites in the rat.

1. After i.v. and intraduodenal administration of 3H-felodipine to rats, approx. 50% of the dose was excreted in bile in the first 6 h. Total urinary and biliary recoveries after both administration routes were similar. 2. Neither unchanged felodipine nor oxidized pyridine metabolite was detected in bile. Bile collection had no effect on the blood concentration-time profiles of either compound. 3. Bile collection decreased the area under the blood concentration-time curve (AUC) of total, unidentified felodipine metabolites by 30%, and their urinary recovery by 50%. 4. Of the total metabolites excreted in bile, 40% was calculated to be subject to enterohepatic recycling. 5. The dose-normalized AUC of both felodipine and pyridine metabolite were decreased after intraduodenal administration of drug, indicating pre-systemic elimination of drug, and possibly of the pyridine, in the gut. Route of administration had no effect on the AUC of total unidentified metabolites.

Pharmacokinetics of a single intravenous and oral dose of pafenolol--a beta 1-adrenoceptor antagonist with atypical absorption and disposition properties--in man.

The pharmacokinetics of pafenolol were studied in eight young healthy individuals. The doses were 10 mg iv and 40 mg orally. Each dose was labeled with 100 microCi [3H]pafenolol. The plasma concentration-time curve of the oral dose exhibited dual maxima. The second peak was about four times higher than the first one. Maximum concentrations were attained after 0.9 +/- 0.2 and 3.7 +/- 0.6 hr. The mean bioavailability (F) of the oral dose was 27.5 +/- 15.5%. The reduction in F was due mainly to incomplete gastrointestinal absorption. The drug was rapidly distributed to extravascular sites; t1/2 lambda 1 was 6.6 +/- 1.8 min. The volumes of distribution were Vc = 0.22 +/- 0.08 liter/kg, Vss = 0.94 +/- 0.17 liter/kg, and Vz = 1.1 +/- 0.16 liters/kg. The iv dose of pafenolol was excreted in unchanged form in the urine to 55.6 +/- 5.1% of the given dose and in the feces to 23.8 +/- 5.7% within 72 hr. The corresponding recoveries of the oral dose were 15.8 +/- 5.9 and 67.0 +/- 10.2%, respectively. About 10% of both doses was recovered as metabolites in the excreta. Approximately 6% of the oral dose was metabolized to nonabsorbable compounds in the intestine. The mean total plasma clearance was 294 +/- 57 ml/min, of which renal clearance, metabolic clearance, and gastrointestinal and/or biliary clearance were responsible for 165 +/- 31, 31 +/- 15, and 95 +/- 32 ml/min, respectively. The half-life of the terminal phase determined from plasma levels up to 24 hr after dosing was 3.1 +/- 0.3 hr for the iv dose and 6.7 +/- 0.7 hr for the oral dose.

Biliary secretion of felodipine metabolites in man after intravenous [14C]felodipine.

The biliary secretion of [14C]felodipine in 4 healthy human subjects was studied by use of the multiple marker dilution principle with double lumen tubes placed in the stomach and intestine. Insignificant amounts of 14C activity were recovered from gastric aspirates. The individual recovery from intestinal aspirates varied from 2.9 to 8.5% of the dose of radioactivity over the period of 4.5 h after dosing. Less than 0.1% was identified as unchanged felodipine. The results show that biliary secretion is a minor route of elimination of felodipine or its metabolites. Bile collection for 4.5 h had no significant effect on the pharmacokinetics of felodipine, although the 72 h urinary recovery of radioactivity tended to be lower when bile was collected (59%) than in the control experiment (66%).