Lack of evidence for polymorphism in metoprolol metabolism.

DeRuiter, Jack; Wilkins, Martin R.; Quarterman, CP

doi:10.1111/j.1365-2125.1983.tb04984.x

Cited by 18 publications

(8 citation statements)

References 20 publications

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“…It was found that for metoprolol, timolol, propranolol and atenolol, 94, 61,8 and 0%, respectively, of the variance in AUC was related to the debrisoquine to 4-hydroxydebrisoquine ratio. However, Jack et al (1983a) have argued that the metabolism of metoprolol is not polymorphic since there is no evidence of bimodality in the frequency distribution of its AUe. With the aid of a computer simulation Jackson et al (1984, and in preparation) have shown that the use of AUC data is an insensitive method for detecting genetic polymorphism when the defect is present in only a small proportion of the population ( fig.…”

Section: Contribution Of Oxidation Phenotype To Variability In Pharmamentioning

confidence: 97%

The Polymorphic Oxidation of ??-Adrenoceptor Antagonists

Lennard

Tucker

Woods

1986

Clinical Pharmacokinetics

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Wide variability in response to some drugs such as debrisoquine can be attributed largely to genetic polymorphism of their oxidative metabolism. Most beta-blockers undergo extensive oxidation. Anecdotal reports of high plasma concentrations of certain beta-blockers in poor metabolisers (PMs) of debrisoquine have claimed that the oxidation of these drugs is under polymorphic control. Subsequently, controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol, timolol and bopindolol. The poor metaboliser phenotype is associated with increased plasma drug concentrations, a prolongation of elimination half-life and more intense and sustained beta-blockade. Phenotypic differences have also been observed in the pharmacokinetics of the enantiomers of metoprolol and bufuralol. In vivo and in vitro studies have identified some of the metabolic pathways which are subject to the defect, viz. alpha-hydroxylation and O-demethylation of metoprolol and 1'- and possibly 4- and 6-hydroxylation of bufuralol. In contrast, the overall pharmacokinetics and pharmacodynamics of propranolol, which is also extensively oxidised, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is lower in poor metabolisers. As anticipated, the disposition of atenolol which is eliminated predominantly unchanged by the kidney and in the faeces, is unrelated to debrisoquine phenotype. The clinical significance of impaired elimination of beta-blockers is not clear. If standard doses of beta-blockers are used in poor metabolisers, these subjects may be susceptible to concentration-related adverse reactions and they may also require less frequent dosing for control of angina pectoris.

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Section: Contribution Of Oxidation Phenotype To Variability In Pharmamentioning

confidence: 97%

The Polymorphic Oxidation of ??-Adrenoceptor Antagonists

Lennard

Tucker

Woods

1986

Clinical Pharmacokinetics

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“…These metabolites possess about one-tenth the i3-blocking activity ofmetoprolol (Borg et al 1975). Genetic polymorphism in metoprolol metabolism was not observed (Horai et al 1989;Jack et al 1983). These data suggest that these active metabolites do not usually contribute to the i3-blocking activity.…”

Section: Pharmacokinetic Datamentioning

confidence: 99%

Metabolites of Antihypertensive Drugs

Ebihara

Fujimura

1991

Clinical Pharmacokinetics

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Many antihypertensive drugs are extensively metabolised in humans. Since some metabolites are active and may therefore contribute to the pharmacological activity of the parent drugs, knowledge of the pharmacokinetic properties of active metabolites is important for understanding the overall effects of drugs. Four categories of antihypertensive drugs with active metabolites are dealt with, with selected examples described in some detail. First, drugs with effects relying totally on active metabolites include agents such as methyldopa, cadralazine and many angiotensin converting enzyme (ACE) inhibitors. Secondly, those with effects primarily due to active metabolites include drugs such as triamterene and spironolactone. Thirdly, agents with effects primarily due to the parent drug, but with active metabolites providing significant contributions to the overall pharmacological effect, include drugs such as indoramin, alprenolol, acebutolol, diltiazem and verapamil. Lastly, agents with pharmacological effects with only minor (if any) contributions from active metabolites include drugs such as propranolol, metoprolol, carteolol and others.

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“…This was also shown to be the case for one minor metabolic pathway of the first available beta blocker propranolol (Lennard el al, 1986) as well as for bufuralol (Dayer et al, 1985) which was never introduced as a drug. There was an unusual debate about the presence or absence of bimodality of metoprolol clearance (Jack et al, 1983;Jack and Wilkins, 1984;Lennard et al, 1984;Idle and Smith, 1984;Regirdh and Johnsson, 1984) but it was unequivocally established that low clearance of metoprolol is related to the phenotype poor metaboliser of debrisoquine (Lennard et al, 1982(Lennard et al, , 1983a. In figure 5 , the relationship between metoprolol plasma concentrations and beta blockade in four rapid metabolisers and in 6 slow metabolisers of debrisoquine is shown in plasma samples drawn at 2, 12 and 24 h after dosing.…”

Section: Beta Blockersmentioning

confidence: 99%

Clinical consequences of polymorphic drug oxidation

Alván

1991

Fundamemntal Clinical Pharma

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Many characters are genetically regulated as polymorphisms. This means that discrete groups are seen within the distribution of a certain character. Drug metabolism is no exception and the polymorphism of acetylation is recognised since the 50's. Polymorphic drug oxidation was discovered in the 70's and has been extensively studied. There are two fully established polymorphisms in drug oxidation named as the debrisoquine/sparteine and the s-mephenytoin hydroxylation polymorphisms. The metabolism of a number of important drugs cosegregates with that of debrisoquine. Among these drugs are beta-blockers, antiarrhythmics, tricyclic antidepressants and neuroleptics. Apart from accumulation of parent drug and active metabolite, also reduced formation of active metabolite occur for some drugs in slow metabolisers. There are, however, few cases where the presence of polymorphic drug metabolism is of significant disadvantage. The polymorphisms will add to variability in drug clearance but the potential clinical importance should be evaluated for each drug. The cytochrome P-450 isozyme responsible for debrisoquine hydroxylation is of high affinity-low capacity character, which means that it can be saturated under certain circumstances. This will decrease the difference in drug metabolic rate between rapid and low metabolisers as will inhibitors of the debrisoquine isozyme like cimetidine, quinidine and propafenone. The debrisoquine isozyme is not readily inducible. In cases where a major metabolic route or the formation of an active metabolite are polymorphically controlled, knowledge about a patient's oxidator status might be of practical value for dose adjustments especially if there is a narrow therapeutic ratio or an established concentration-effect relationship. For some drugs it is difficult to differentiate between insufficient therapeutic effect and symptoms of overdosage. Tricyclic antidepressants and neuroleptics meet some of these criteria and patients who get recurrent treatment may benefit if the physician has knowledge about debrisoquine metabolic phenotype. Otherwise, the clinical consequences of polymorphisms in drug oxidation seem so far to be limited, considering that a number of disease conditions have not shown any clear association with oxidation status. The polymorphisms in drug metabolism should be considered as a part of natural variability which could in fact be larger with other drugs that do not show polymorphic elimination.

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Lack of evidence for polymorphism in metoprolol metabolism.

Cited by 18 publications

References 20 publications

The Polymorphic Oxidation of ??-Adrenoceptor Antagonists

The Polymorphic Oxidation of ??-Adrenoceptor Antagonists

Metabolites of Antihypertensive Drugs

Clinical consequences of polymorphic drug oxidation

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