Genetically Determined Adverse Drug Reactions Involving Metabolism

Abstract

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.

CYP2D6 Mutations and Therapeutic Outcome in Schizophrenic Patients

“…All are structurally related compounds, including many antipsychotics and antidepressants, 5 cardiovascular drugs including several ␤-receptor antagonists, 6 and class I antiarrhythmic agents. 7 Serious drug toxicity [8][9][10] and lack of efficacy of prodrugs 11 are reported in PMs.…”

Advances in Machine Learning Prediction of Toxicological Properties and Adverse Drug Reactions of Pharmaceutical Agents

“…The key critical events frequently involve exposure [98,99], environmental factors [98], genetic factors [100][101][102], and complex interactions involving formation of reactive metabolites, metabolism by P450 isoforms, preponderance of P450 inducers, and occurrence of clinically significant pharmacokinetic interactions with co-administered drugs [97]. These complicated factors individually and collectively affect the level of toxicity of drugs, which may not be adequately represented by currently available molecular descriptors that are based primarily on physicochemical properties of drugs.…”

Clinical significance of therapeutic drug monitoring in pharmacotherapy rationalization and individualization

“…Možnosť geneticky determinovaného rýchleho, alebo pomalého metabolizmu je faktorom, s ktorým uvažujeme u pacienta, u ktorého lieková plazmatická hladina je zreteľne nízka, alebo vysoká s tou, ktorú očakávame. Incidencia geneticky podmieneného rýchleho metabolizmu je vyššia ako incidencia pomalého metabolizmu lieku (21,22,23,24,25,26,27,28,29,40,41,42,45).…”