James McAinsh

Metabolism of atenolol in man.

1. The disposition and metabolism of 1-(4-carbamoyl[14C]methylphenoxy)-3-isopropylaminopan-2-ol (atenolol, Tenormin) has been studied in man following oral and intravenous doses. 2. Approx. 50% of an oral dose was eliminated in urine; the major radiolabelled component was atenolol (approx. 90%). Faecal extracts also contained largely unchanged atenolol, with small amounts of more polar metabolites. Biliary excretion of atenolol and its metabolites is not a major route of elimination in man. Metabolism of the compound is not extensive and route-dependent modes of metabolism do not appear to complicate the position. 3. Atenolol appeared to be the only major radiolabelled component in blood. 4. Oral doses of atenolol are incompletely absorbed (range 46-62%), even when formulated as a solution. 5. 1-[4-(C-Carbamoylhydroxymethyl)phenoxy]-3-isopropylaminopropan-2-ol was a minor urinary metabolite, which has only one tenth the activity of the parent compound as a beta-adrenergic blocking agent in the rat. 6. Pharmacological activity in man appears to be due to atenolol alone.

Relationship between blood level of atenolol and pharmacologic effect

Thirty‐five hypertensive patients were treated with atenolol in weekly increasing doses (25, 50, 100, and 200 mg thrice daily). Factors determining the blood level of the drug were studied along with the relationship between blood level, the degree of cardiac beta blockade, and the antihypertensive effect of the drug. The blood level obtained varied with the daily dose, the time of blood sampling during the day, the body weight, and the creatinine clearance. The degree of beta blockade was assessed by measuring maximum‐exercise tachycardia and was correlated with the blood level of atenolol. The reduction of the maximum exercise heart rate was independent of age. The hypotensive effect was not closely correlated with the blood level. Three days after the termination of long‐term atenolol treatment, blood levels and beta blockade were still detectable.

Theoretical Michaelis — Menten elimination model for propranolol

SummaryA pharmacokinetic model, with Michaelis-Menten elimination, has been developed for drugs and propranolol in particular. The theory is given and the relationship between the area under the theoretical plasma level curve and the absorption rate constant is discussed. This approach allows for an explanation of many of the observed pharmacokinetics of “Inderal” 1 and particularly ”Inderal“ LA ; a sustained release preparation of propranolol. In particular, the bioavailability, as measured by area under the curve, is found to be strongly dependent on the absorption half-life in agreement with experimentally observed data.

Absolute bioavailability study in the dog with Visacor, a new cardioselective beta blocking drug with intrinsic sympathomimetic activity.

SummaryThe cardioselective beta-adrenergic blocking drμg Visacor (ICI 141,292) was dosed to six beagle dogs in a randomized cross-over manner. Five formulations were examined i.e. a 15 mg/kg intravenous solution, a 50 mg/kg oral solution, and 50, 100 and 200 mg/kg oral powder formulations. Whole blood and urine samples were collected at various times after each dose and analysed for parent drμg concentration by a high pressure liquid chromatography procedure. The urine samples were also analysed for parent drμg content after hydrolysis with β-glucuronidase.The normalised intravenous blood levels of ICI 141,292 were found to decay tri-exponentially with a final phase elimination half-life of about 10 h. The computer fitted data showed the drμg to possess a high volume of distribution for both the central compartment (54% body weight) and whole body (1384% body weight) indicating the possibility of a high degree of metabolism. The drμg clearance following i.v. administration was 196 ml/min and the urinary recovery rate of parent drμg was 24% (unhydrolysed) and 40% following hydrolysis with β-glucuronidase.Following oral dosing at 50 mgAg (as both powder (C) and solution (B)), 100 (D) and 200 (E) mg/kg (as powder) the systemic blood profiles were found to increase with dose. The mean peak blood level attained was 6± 1, 5± 1, 8± 1 and 14±1 μg/ml for formulations, B, C, D and E respectively. The systemic bioavailability of ICI 141,292 was only about 40%. The areas under the curves increased linearly with dose and the elimination phase half-life was unchanged with dose. The calculated half-life (7 h) was apparently shorter after oral administration than after intravenous administration (10 h) but this is probably an artefact dependent on the limit of detection of the assay procedure. At 50 mg/kg there were no significant differences in blood profiles or in the urinary excretion of drμg between the solution and powder formulations. However the overall systemic bioavailability was marginally higher with the powder.These observations are consistent for a drμg which is cleared by both renal and hepatic elimination processes, which undergoes “first-pass” metabolism on oral dosing and, over the oral dose range studied, obeys linear pharmacokinetics. The significant increase in recovery of parent drμg, after hydrolysis of the urine with β-glucuronidase, indicates that the ICI 141,292 glucuronide conjμgate is present to a significant extent. The results also demonstrate that absorption of parent drμg from the gastrointestinal tract may not be complete.