Metabolism of Atenolol in Man

1 Plasma levels of atenolol and metoprolol and their effects on exercise heart rate have been studied after oral administration of single doses of 100 mg of the two drugs in ordinary tablets alone and during concomittant cimetidine medication of 1 g per day.2 Cimetidine caused no significant changes in the bioavailability of any of the two p-adrenoceptor blockers and the rate of elimination of metoprolol was unaffected by the histamine H2-receptor blocker. A slight but significant increase in the elimination half-life from 6.5 + 0.6 to 7.9 0.6 (P < 0.05) was noted for atenolol after pretreatment with cimetidine. The f3-adrenoceptor blocking effect was about the same for the used doses of atenolol and metoprolol and it was not changed during cimetidine therapy.

Section: Pharmacokineticsmentioning

confidence: 57%

“…Metoprolol is mainly eliminated by metabolism (Regardh & Johnsson, 1981) whereas atenolol is excreted to about 90% in unchanged formn in the urine (Reeves et al, 1978). after an overnight fast of 10 h. The dose was taken with 50 ml of water.…”

Section: Introductionmentioning

confidence: 99%

The effect of pretreatment with cimetidine on the bioavailability and disposition of atenolol and metoprolol.

Jj¹,

Streurman²,

Regårdh³

1982

“…Their patients maintained a relative whole body clearance of atenolol (38 + 10 ml min-' 1.73 m-2); in our patients, atenolol renal clearance is very low (4.6 + 1.5 ml/min) and in good agreement with creatinine clearance. These values can be compared because atenolol is almost entirely renally excreted (Fitzgerald et al, 1978;Flouvat et al, 1978), and predominantly in the unchanged form (Reeves, McAinsh, McIntosh & Winrow, 1978 (Eastwood, Curtis & Smith, 1973). During haemodialysis, the mean apparent plasma half-life of atenolol (7.5 h) is significantly lower (P<0.001) than the average value after dialysis (51.2 h) and in patients not yet dialysed (73.4 h).…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetics of atenolol in patients with terminal renal failure and influence of haemodialysis.

Flouvat¹,

Decourt²,

Aubert³

et al. 1980

1 The pharmacokinetics of atenolol, after 200 mg orally, were studied in 18 patients with terminal renal insufficiency (creatinine clearance less than 5 ml/min), of whom twelve were being treated by chronic dialysis. 2 The peak plasma level, 1.59 +/‐ 0.43 mg/l, was reached in 4.7 +/‐ 2.1 h. 3 Without dialysis treatment, the apparent plasma half‐ life of atenolol was greatly increased (73.4 +/‐ 28.8 /). During dialysis, it dropped to 7.5 +/‐ 3.7 h but returned to 51.2 +/‐ 17.3 h after dialysis. The plasma atenolol plot was a rising slope for a few hours after the end of dialysis. 4 Renal clearance of atenolol was very low (4.6 +/‐ 1.5 ml/min). 5 Plasma clearance during dialysis was 42.6 +/‐ 21.3 ml/min for a mean blood flow‐rate of 236 +/‐ 25 ml/min through a cuprophane membrane dialyser. 6 These results suggest that dosage should be modified for these patients.

“…For example, the plasma clearance of a lipophilic f8-adrenoceptor blocker such as propranolol is almost entirely dependent upon hepatic clearance (Foulkes & Siddall, 1975) and is therefore sensitive to changes in hepatic enzyme activity. On the other hand, watersoluble /3-adrenoceptor blockers such as atenolol are excreted largely unchanged into urine (Reeves et al, 1978) and consequently the clearance of such a drug is insensitive to changes in enzyme activity. Consistent with this hypothesis, it has been demonstrated that plasma antipyrine clearance and cytochrome P-450 content in liver biopsies were related to the rate of propranolol elimination but not to sotalol, which is excreted unchanged (Sotaniemi et al, 1979).…”

Section: Pharmacokinetics Of Drug Interactionsmentioning

confidence: 99%

Prediction of metabolic drug interactions involving beta‐adrenoceptor blocking drugs.

Park¹

1984

1 There is evidence, from human and animal studies, that drug-metabolising enzymes exist in multiple forms, the individual enzymes having selective, but not specific, substrate requirements. Consequently drug interactions may arise when two drugs bind to the same enzyme. The degree of enzyme inhibition will be partly dependent on the relative affinities of the drugs for the enzyme and on their rates of turnover. The decrease in drug clearance produced by enzyme inhibition is dependent on the fraction of the drug normally metabolised by the inhibited pathway(s). 2 Cimetidine, a P-450 enzyme inhibitor, increases the systemic bioavailability of propranolol and labetalol, which undergo extensive metabolism, but does not affect the clearance of atenolol, which is excreted largely unchanged. In this situation, both the extent and type of biotransformation are important. Thus, cimetidine has no effect on the clearance of penbutolol, even though the drug is eliminated almost entirely by biotransformation. The major metabolite is penbutolol glucuronide, and it has been shown recently that cimetidine does not inhibit glucuronylation. 3 f3-adrenoceptor blockers also act as enzyme inhibitors themselves. For example, antipyrine clearance is decreased by propranolol and to a lesser extent by metoprolol, whereas atenolol has no effect. It has been suggested, therefore, that there is a relationship between the lipid-solubility of 18-adrenoceptor blockers and their ability to inhibit drug metabolism.4 The clearance of lipophilic ,3-adrenoceptor blockers is dependent on hepatic enzyme activity, and is therefore sensitive to enzyme induction. For drugs with high hepatic clearance and subsequent high presystemic elimination, a moderate increase in the extraction ratio will produce a marked decrease in systemic bioavailability. Thus pentobarbitone enzyme induction increased the hepatic extraction of alprenolol by 29% and decreased the AUC by 78%. 5 The impact of changes in the activity of the drug-metabolising enzymes on drug clearance is dependent upon the extent and type of biotransformation(s) that the interacting drugs undergo. A better understanding of such drug interactions will be obtained by measuring metabolite formation rather than clearance of parent drug.