Why hypertensive patients vary in their response to oral debrisoquine.

Silas, J H; Lennard, M. S.; Tucker, GT; Smith, A. J.; Malcolm, S L; Marten, T. R.

doi:10.1136/bmj.1.6058.422

Cited by 40 publications

(13 citation statements)

References 12 publications

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“…The clinical features of thirteen of these have been reported (Silas et al, 1977); those of the two remaining subjects were similar. Tablet counts confirmed that each subject took more than 95%o of the tablets prescribed.…”

Section: Subjectsmentioning

confidence: 83%

“…Almost 70% of the variance in response to debrisoquine may be related to differences in its urinary recovery and plasma concentration and there is a significant inverse correlation between the urinary recovery of its 4-hydroxy metabolite (HD) and the fall in blood pressure. Thus a poor response can be overcome by increasing the dose (Silas, Lennard, Tucker, Smith, Malcolm & Marten, 1977).…”

Section: Introductionmentioning

confidence: 99%

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The disposition of debrisoquine in hypertensive patients.

Silas¹,

Lennard²,

Tucker³

et al. 1978

Brit J Clinical Pharma

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I The urinary recovery and plasma concentration of debrisoquine (D) and its metabolite 4-hydroxydebrisoquine (HD) has been studied following single and multiple oral administration of debrisoquine hemisulphate to 15 hypertensive in-patients and four normal volunteers. The distribution of D in the blood was studied after a single dose to one volunteer. The greatest concentration of the drug was in the platelet rich fraction from which it was eliminated slowly. The elimination half-lives in plasma and platelet rich plasma were 17.5 h and 56 h respectively. 7 On early multiple dosing the hypotensive response was related to high plasma D concentrations.

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Section: Subjectsmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

The disposition of debrisoquine in hypertensive patients.

Silas¹,

Lennard²,

Tucker³

et al. 1978

Brit J Clinical Pharma

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“…Its prescription has however been complicated by a large interpatient variation (40-fold) in optimal dose requirement. \, 12 We have shown that variation in response to debrisoquin is largely due to genetically determined variations in metabolism. 4 Debrisoquin is metabolized and inactivated in man mainly by alicyclic 4-hydroxylation, with a small proportion oxidized in the aromatic ring to yield 4 phenolic metabolites, namely, 5-, 6-, 7-, and 8-hydroxydebrisoquin.3 The extent to which the drug is hydroxylated in the 4-position in Caucasian subjects is controlled by a single autosomal gene locus and demonstrates polymorphism,8 There are 2 apparent phenotypes within the popUlation: The first small recessive phenotype (8% of Caucasians) is characterized by an almost total inability to 4-hydroxylate the drug and is designated the poor metabolizer (PM) phenotype.…”

mentioning

confidence: 99%

Debrisoquin hydroxylation polymorphism among Ghanaians and Caucasians

Woolhouse

Andoh

Mahgoub

et al. 1979

Clin Pharma and Therapeutics

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The alicyclic and aromatic hydroxylation of debrisoquin was studied in Ghanaians. As in a previously studied Caucasian population, the alicyclic 4-hydroxylation of debrisoquin in Ghanaians was polymorphic. Three phenotypes were observed: homozygous extensive metabolizers (58%), heterozygous extensive metabolizers (36%), and homozygous poor metabolizers (6%). In contrast, British Caucasians are primarily monomorphic extensive metabolizers (92%) and homozygous poor metabolizers comprise 8% of the population. Urinary recovery of the drug and its hydroxylated metabolites was significantly less in the Ghanaian subjects. In both Ghanaian and British populations, aromatic hydroxylation producing 5-, 6-, 7-, and 8-hydroxydebrisoquin was shown to parallel the alicyclic 4-hydroxylation of debrisoquin, and thus to be controlled by the same gene locus. Debrisoquin is advocated as a tool for uncovering polymorphism in drug oxidation and its interethnic variations.

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“…Debrisoquine is an antihypertensive agent whose widely variable plasma concentrations and blood pressure-lowering effect over a narrow dose range are largely determined by its polymorphic oxidation (Silas et al 1977). This is now more of academic than of clinical significance, since debrisoquine and other adrenergic neurone blocking agents are now rarely used in the treatment of hypertension because of the risk of orthostatic hypotension and other adverse effects.…”

Section: Cardiovascular Drugsmentioning

confidence: 98%

Genetically Determined Adverse Drug Reactions Involving Metabolism

Lennard

1993

Drug Safety

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Genetic factors represent an important source of interindividual variation in drug response. Relatively few adverse drug effects with a pharmacodynamic basis are known, and most of the well characterised inherited traits take the form of genetic polymorphisms of drug metabolism. Monogenic control of N-acetylation, S-methylation and cytochrome P450-catalysed oxidation of drugs can have important clinical consequences. Individuals who inherit an impaired ability to perform one or more of these reactions may be at an increased risk of concentration-related toxicity. There is a strong case for phenotyping before starting treatment with a small number of drugs that are polymorphically N-acetylated or S-methylated. However, the issue of clinical significance is perhaps most relevant for the debrisoquine oxidation polymorphism, which is mediated by cytochrome CYP2D6 and which determines the pharmacokinetics of many commonly used drugs. Phenotypic poor metabolisers of debrisoquine (8% of Caucasian populations) taking standard doses of some tricyclic antidepressants, neuroleptics or antiarrhythmic drugs may be particularly prone to adverse reactions. Similarly, clinically relevant drug interactions between these drugs and other substrates of cytochrome CYP2D6 may occur in the majority of the population who are extensive metabolisers. However, it is clear that in the majority of cases there is a need for controlled prospective studies to determine clinical significance. Accordingly, routine debrisoquine phenotyping or genotyping before beginning drug treatment is difficult to justify at present, although it may be helpful in individual cases. When prescribing drugs whose metabolism is polymorphic alone or in combination, careful titration of the dose in both phenotypic groups is prudent. In some cases it will be preferable to use alternative therapy to avoid the risk of adverse drug reactions.

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Why hypertensive patients vary in their response to oral debrisoquine.

Cited by 40 publications

References 12 publications

The disposition of debrisoquine in hypertensive patients.

The disposition of debrisoquine in hypertensive patients.

Debrisoquin hydroxylation polymorphism among Ghanaians and Caucasians

Genetically Determined Adverse Drug Reactions Involving Metabolism

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