Lack of effect of atenolol on antipyrine clearance.

The effects of separate 1 week pre‐treatments with each of the beta‐ adrenoceptor antagonists, propranolol (80 mg every 12 h), metoprolol (100 mg every 12 h) and atenolol (50 mg once daily), on the disposition of a single i.v. dose of tolbutamide were studied in six healthy volunteers. In addition, the effects of a 1 week pre‐treatment with metoprolol (100 mg every 12 h) and atenolol (50 mg once daily) on the disposition of orally and i.v. administered lignocaine were determined in seven healthy subjects. Tolbutamide clearance, half‐life, volume of distribution and plasma protein binding were not altered by the beta‐ adrenoceptor blocker pre‐treatments. Similarly, neither metoprolol nor atenolol had a significant effect on the systemic clearance, apparent oral clearance or other dispositional parameters of lignocaine. ‘Therapeutic’ plasma concentrations of the beta‐adrenoceptor blockers were confirmed on each study day. It is concluded that the inhibition of oxidative drug metabolism previously reported for lipophilic beta‐ adrenoceptor blockers may be selective for different forms of cytochrome P450 and possible concentration‐dependent.

Section: Introductionmentioning

confidence: 99%

Failure of ‘therapeutic’ doses of beta‐adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine.

Miners¹,

Wing²,

Lillywhite³

et al. 1984

“…Introduction P-adrenoceptor antagonists have been shown to inhibit hepatic oxidative metabolism in vitro and in vivo to an extent dependent upon their lipid solubility (Bax et al, , 1983; Deacon et al, 1981;Tucker et al, 1982;Al-Asady et al, 1982). Penbutolol is the most lipid soluble of the P-adrenoceptor antagonists used clinically.…”

mentioning

confidence: 99%

Penbutolol and propranolol: a comparison of their effects on antipyrine clearance in man.

Bax¹,

Jones²,

Lennard³

et al. 1985

Self Cite

“…For example, individuals vary markedly in their ability to hydroxylate metoprolol, and it has been shown that the metabolism of metoprolol exhibits the debrisoquine type of genetic polymorphism (Lennard et al, 1982). This finding emphasises the need to investigate the metabolism of f3-adrenoceptor blockers in panels of phenotyped subjects, in order to assess the importance of a particular metabolic variable.…”

Section: Metabolism Of 83-adrenoceptor Blockersmentioning

confidence: 99%

“…Antipyrine clearance is also reduced by metoprolol, whereas atenolol has no effect . It has been suggested, therefore, that there is a relationship between the lipid-solubility of /3-adrenoceptor blockers and their ability to inhibit drug metabolism (Deacon et al, 1981;Tucker et al, 1982).…”

Section: Enzyme Inhibitionmentioning

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.