Genetically Determined Variations in Drug Disposition and Response in Man

Vesell, Elliot S.

doi:10.1007/978-3-642-46314-3_7

Cited by 4 publications

(2 citation statements)

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“…The majority of known inherited traits, or 'inborn errors' as they have been termed, that result in drug toxicity are caused by alterations in the functional activity of an enzyme. Two of the earliest to be characterised were glucose-6-phosphate dehydrogenase deficiency and porphyria (Vessell 1975).…”

Section: Discussionmentioning

confidence: 99%

“…Treatment with succinylcholine, a short-acting muscle relaxant, leads to prolonged apnoea in about I in 10 000 individuals (Vessell 1975). In this rare Correlation between thiopurine methyltransferase (TPMT) activity and 6-thioguanine nucleotide (6-TGN) concentration in 95 children with acute lymphoblastic leukaemia undergoing 6-mercaptopurine remission chemotherapy; RBC = red blood cell; rs = Spearman rank correlation coefficient (from Lennard et al 1990, with permission).…”

Section: Atypical Pseudocholinesterasementioning

confidence: 97%

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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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Section: Discussionmentioning

confidence: 99%

Section: Atypical Pseudocholinesterasementioning

confidence: 97%