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. 1984;17(Suppl 1):3S–9S. doi: 10.1111/j.1365-2125.1984.tb02422.x

Prediction of metabolic drug interactions involving β-adrenoceptor blocking drugs

B K Park
PMCID: PMC1463283  PMID: 6146338

Abstract

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 β-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 β-adrenoceptor blockers and their ability to inhibit drug metabolism.

4 The clearance of lipophilic β-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.

Keywords: antipyrine, β-adrenoceptor blockers, biotransformation, pharmacodynamics, pharmacokinetics

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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