The interaction of cimetidine with metoprolol, atenolol, propranolol, pindolol and penbutolol [letter]

Spahn, H.; Kirch, Wilhelm; Mutschler, E.

doi:10.1111/j.1365-2125.1983.tb01539.x

Cited by 8 publications

(2 citation statements)

References 5 publications

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“…Thus cimetidine had no effect on the AUC of penbutolol, a drug which is almost totally eliminated by biotransformation. The major metabolite of penbutolol is, however, penbutolol glucuronide (Spahn et al, 1983a). It has been shown that cimetidine reduces the clearance of drugs which undergo oxidative biotransformations (antipyrine, diazepam) but not that of drugs (paracetamol, lorazepam) which are mainly conjugated (Abemethy et al, 1983). Indeed, it was shown that hydroxylation of penbutolol, a minor biotransformation, was blocked by cimetidine (Spahn et al, 1983a).…”

Section: Enzyme Inhibitionmentioning

confidence: 99%

“…The major metabolite of penbutolol is, however, penbutolol glucuronide (Spahn et al, 1983a). It has been shown that cimetidine reduces the clearance of drugs which undergo oxidative biotransformations (antipyrine, diazepam) but not that of drugs (paracetamol, lorazepam) which are mainly conjugated (Abemethy et al, 1983). Indeed, it was shown that hydroxylation of penbutolol, a minor biotransformation, was blocked by cimetidine (Spahn et al, 1983a). However this argument does not explain why cimetidine reduces the clearance of labetalol, which is metabolised to a mixture of three glucuronides (Martin et al, 1978).…”

Section: Enzyme Inhibitionmentioning

confidence: 99%

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

Park¹

1984

Brit J Clinical Pharma

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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.

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Section: Enzyme Inhibitionmentioning

confidence: 99%

Section: Enzyme Inhibitionmentioning

confidence: 99%

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

Park¹

1984

Brit J Clinical Pharma

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Interaction of bisoprolol with cimetidine and rifampicin

Kirch

Röse

Klingmann

et al. 1986

Eur J Clin Pharmacol

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In 6 healthy volunteers the pharmacokinetics of bisoprolol under steady-state conditions was investigated over three consecutive phases: over 7 days of 10 mg of bisoprolol once daily per os, 7 days of 10 mg of bisoprolol once daily plus 400 mg of cimetidine t.i.d. and 14 days of 10 mg of bisoprolol and 600 mg of rifampicin once daily with adequate intervals free of medication. After therapy with bisoprolol alone peak plasma levels (Cssmax) of the beta-blocker were 55.5 +/- 6.4 ng/ml (means +/- SEM), area under the plasma level-time curve (AUC tau) was 597 +/- 70 ng/ml.h, total body clearance (CL) 15.8 +/- 1.8 l/h and elimination half-lives (t1/2 beta) 10.1 +/- 1.2 h. Cimetidine did not cause any significant changes in the pharmacokinetics of bisoprolol. Co-administration of rifampicin resulted in a decrease in Cssmax (43.0 +/- 6.9 ng/ml), AUC tau (397 +/- 54 ng/ml X h) and t1/2 beta (6.2 +/- 0.4 h). Accordingly, total body clearance increased to 23.8 +/- 2.5 l/h (p less than 0.05). In conclusion bisoprolol showed a statistically significant but probably clinically not important interaction with the enzyme-inducing drug rifampicin, but not with the enzyme inhibitor cimetidine.

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Adverse Reactions and Interactions with β-Adrenoceptor Blocking Drugs

Lewis

McDevitt

1986

Medical Toxicology

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beta-Blocking drugs are widely used throughout the world and serious adverse reactions are relatively uncommon. Most of those which do occur are pharmacologically predictable and may be avoided by ensuring that patients who are to be given beta-blockers do not have a predisposition to the development of bronchospasm, cardiac failure or peripheral ischaemia. In some situations, the use of a beta 1-selective blocking drug may reduce the risk of a severe adverse reaction, but there is little evidence that other ancillary properties such as partial agonist activity are of relevance in this context. Long term experience with many of the beta-blockers in current use suggests that unpredictable major adverse reactions such as the practolol oculomucocutaneous syndrome are unlikely to be repeated, although some of these drugs may be associated with immunological disturbances and some have been implicated in the development of retroperitoneal fibrosis. beta-Blocking drugs appear to be associated with a number of subjective side effects including muscle fatigue, peripheral coldness and some neurological symptoms. These side effects are highly subjective and are therefore difficult to quantify and it is not known whether they are of major importance in terms of their effect upon patients' overall well-being. It cannot be assumed that simply because such side effects can be elicited that they do, in fact, matter. However, because beta-blockers are often prescribed for patients who have no symptoms and for whom the benefits of therapy are generally small, such side effects would be of considerable importance if they had an overall effect upon quality of life. There are theoretical reasons to suppose that the incidence and severity of such side effects may be related to the ancillary properties of the individual drugs, but there is little evidence that parameters such as beta 1-selectivity, or partial agonist activity are clinically important determinants of the severity of these side effects. Lipophilicity, however, may be associated with an increased incidence of neurological symptoms. beta-Blocking drugs may cause a variety of metabolic disturbances including an increase in serum VLDL-cholesterol concentrations. However, long term studies have not shown that such disturbances are associated with an increased risk of cardiovascular disease, indicating that such metabolic changes may not be of major importance in practice. beta-Blocking drugs may be involved in a number of interactions with other drugs, but few of these have been shown to be of clinical significance.(ABSTRACT TRUNCATED AT 400 WORDS)

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The interaction of cimetidine with metoprolol, atenolol, propranolol, pindolol and penbutolol [letter]

Cited by 8 publications

References 5 publications

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

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

Interaction of bisoprolol with cimetidine and rifampicin

Adverse Reactions and Interactions with β-Adrenoceptor Blocking Drugs

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