The expanding role of gene-based prescribing for phase II drug-metabolizing enzymes

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Clinical pharmacogenomics has expanded rapidly with the ability to translate evidence from basic science findings into actionable decisions guiding pharmacotherapy in – various disease states. Most findings with potential clinical relevance have been in drug-metabolizing enzymes where variation could cause interindividual differences in response and efficacy. Conventionally, these metabolizing enzymes are classified as Phase I and Phase II enzymes. Although Phase II enzymes are responsible for the metabolism of many drugs, research has focused more on variation in Phase I enzymes. Our aim in this review was to discuss from a historical to present context, the research on key variants in major Phase II enzymes and to summarize clinical pharmacogenetic association studies that could help guide future translation into practice. We evaluated pivotal articles in PubMed (1980–2022) on human pharmacogenomic studies (preclinical and clinical) of N-acetyltransferases (NATs), methyltransferases, glutathione transferases, sulfotransferases, and glucuronosyltransferases for the evidence of clinical applicability and utility. Of the 5 Phase II enzyme superfamilies reviewed, there is presently evidence to support clinical utility for gene-based prescribing for two of them. A third family (NATs) is evaluated as having strong likelihood for future utility in the pharmacological treatment of acquired immunodeficiency syndrome-associated opportunistic infections, tuberculosis, and endemic diseases.