Optimising Seniors’ Metabolism of Medications and Avoiding Adverse Drug Events Using Data on How Metabolism by Their P450 Enzymes Varies with Ancestry and Drug–Drug and Drug–Drug–Gene Interactions

Abstract

Many individuals ≥65 have multiple illnesses and polypharmacy. Primary care physicians prescribe >70% of their medications and renew specialists’ prescriptions. Seventy-five percent of all medications are metabolised by P450 cytochrome enzymes. This article provides unique detailed tables how to avoid adverse drug events and optimise prescribing based on two key databases. DrugBank is a detailed database of 13,000 medications and both the P450 and other complex pathways that metabolise them. The Flockhart Tables are detailed lists of the P450 enzymes and also include all the medications which inhibit or induce metabolism by P450 cytochrome enzymes, which can result in undertreatment, overtreatment, or potentially toxic levels. Humans have used medications for a few decades and these enzymes have not been subject to evolutionary pressure. Thus, there is enormous variation in enzymatic functioning and by ancestry. Differences for ancestry groups in genetic metabolism based on a worldwide meta-analysis are discussed and this article provides advice how to prescribe for individuals of different ancestry. Prescribing advice from two key organisations, the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium is summarised. Currently, detailed pharmacogenomic advice is only available in some specialist clinics in major hospitals. However, this article provides detailed pharmacogenomic advice for primary care and other physicians and also physicians working in rural and remote areas worldwide. Physicians could quickly search the tables for the medications they intend to prescribe.

Most patients with disorders of gut‐brain interaction receive pharmacotherapy with major or moderate drug‐gene interactions

“…Second, we integrated the widely accepted Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 and CYP2C19 , which infer the metabolizer phenotype from allelic variants of these genes, 22 with the widely used Flockhart Table 23 that provides a list of medications that are metabolized by cytochrome P450 enzymes (Figure 1). 24 CPIC guidelines categorize CYP2D6 and CYP2C19 metabolizer phenotypes as follows: ultrarapid metabolizer (UM), normal metabolizer (NM), intermediate metabolizer (IM), and poor metabolizer (PM). For our analysis, we grouped NM with UM (NM/UM) and PM with IM (PM/IM) for both pharmacogenes.…”

Multi-Year Retrospective Analysis of Mortality and Readmissions Correlated with STOPP/START and the American Geriatric Society Beers Criteria Applied to Calgary Hospital Admissions

“…For example, two thirds of anti-depressants are metabolised by two isoforms, CYP2C19 and CYP2D6. Patients with the CYP2C19 Null/Null genotype have 0% metabolic activity for medications that are metabolised by the CYP2C19 P450 isoform, whereas those with CYP2C 19*17/*17 have two ultrarapid metabolising alleles, and they metabolise at 120% of the normal rate; for the CYP2D6WtX3 genotype (which has two ultrarapid alleles), the metabolic rate is 150% [24,25].…”

Role of Drug–Gene Interactions and Pharmacogenetics in Simvastatin-Associated Pulmonary Toxicity

“…After absorption, statins are transported into hepatocytes by organic anion transport polypeptides (OATPs) and metabolized by cytochrome P450 (CYP) enzymes [ 12 ]. Genes encoding drug transporters and drug metabolizing enzymes are subject to polymorphisms, which may affect pharmacokinetics and serum drug levels, and subsequently have an impact on the degree of efficacy and toxicity [ 12 , 13 ].

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