Pharmacogenomics of acetaminophen in pediatric populations: a moving target

Abstract

Acetaminophen (APAP) is widely used as an over-the-counter fever reducer and pain reliever. However, the current therapeutic use of APAP is not optimal. The inter-patient variability in both efficacy and toxicity limits the use of this drug. This is particularly an issue in pediatric populations, where tools for predicting drug efficacy and developmental toxicity are not well established. Variability in toxicity between age groups may be accounted for by differences in metabolism, transport, and the genetics behind those differences. While pharmacogenomics has been revolutionizing the paradigm of pharmacotherapy for many drugs, its application in pediatric populations faces significant challenges given the dynamic ontogenic changes in cellular and systems physiology. In this review we focused on the ontogenesis of the regulatory pathways involved in the disposition of APAP and on the variability between pediatric, adolescent, and adult patients. We also summarize important polymorphisms of the pharmacogenes associated with APAP metabolism. Pharmacogenetic studies in pediatric APAP treatment are also reviewed. We conclude that while a consensus in pharmacogenetic management of APAP in pediatric populations has not been achieved, a systems biology based strategy for comprehensively understanding the ontogenic regulatory pathway as well as the interaction between age and genetic variations are particularly necessary in order to address this question.

Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent–Metabolite Population Pharmacokinetic Model

“…3): $$P_i={\theta }_{\text{pop}}\times {\left(\frac{{\text{COV}}_i}{{\text{COV}}_{\text{mean}}}\right)}^{\theta \text{cov}}\times {\mathrm{e}}^{{\eta }_i},$$ where P i is the individual pharmacokinetic parameter for an individual with covariate value COV i , θ pop is the population value for P when COV i equals the mean covariate value COV mean , θ cov is the covariate effect, and η i is the between-subject random effect on P for individual i . Given the potential for genetically mediated differences in paracetamol metabolism [28, 29], race and ethnicity were tested on all metabolite formation clearances (Eq. 2).…”

Best Practices for Management of Pain, Swelling, Nausea, and Vomiting in Dentoalveolar Surgery

“…The analgesic effects of this drug are created by it acting centrally by raising the pain threshold through what is thought to be inhibition of the nitric oxide pathway mediated by a variety of neurotransmitters, including N-methyl-D-aspartate and substance P. Although acetaminophen is one of the oldest and most widely prescribed analgesic drugs, its analgesic efficiency has been found to be improved by combining it with NSAID medications, such as ibuprofen. [21][22][23][24] These new combination medications or just combining them on your own may obviate or decrease the need for narcotic use in many patients.…”

Genetic Association of Single Nucleotide Polymorphisms with Acetaminophen-Induced Hepatotoxicity

“…The current model of acetaminophen-induced hepatic necrosis links the NAPQI-protein adducts with amplified cascades of reactive oxygen and nitrogen species, resulting in the swift loss of hepatic cells and liver function (Ramachandran and Jaeschke, 2017;Wang et al, 2017). This model has been reviewed thoroughly (Russmann et al, 2009(Russmann et al, , 2010Hinson et al, 2010;Fontana, 2014;Krasniak et al, 2014), but in brief, the reactive oxygen species/reactive nitrogen species induce increased mitochondrial permeability, resulting in impaired mitochondrial function (McGill et al, 2012;Jiang et al, 2015) and leading to the initiation of massive necrotic cell death. Subsequently, necrotic hepatocytes release damageassociated molecular patterns resulting in an immune response mediated by various cytokines and innate immune cells (Bourdi et al, 2007;Wang et al, 2015;Fannin et al, 2016).…”

“…These findings confirm that some healthy individuals experience mild to severe liver injury in response to therapeutic doses of acetaminophen, suggesting that genetic components are involved in acetaminophen metabolism. Thus, several groups have proposed that NAPQI toxicity can be enhanced by alterations in the metabolism of acetaminophen due to genetic polymorphisms in the corresponding enzymes (Adjei et al, 2008;Zhao and Pickering, 2011;Krasniak et al, 2014). Single nucleotide polymorphisms (SNPs) in metabolic enzymes have been predicted to explain both the ethnic and interindividual differences in acetaminophen degradation and hepatotoxicity (Critchley et al, 1986(Critchley et al, , 2005.…”

“…This concept is not unique to acetaminophen-induced hepatotoxicity, as genetic variations in cellular stress, drug metabolism, and immune response genes are associated with DILI susceptibility (Daly and Day, 2012;Chen et al, 2015). Numerous SNPs have been identified that alter the activity of drug-metabolizing enzymes, including SULT, UGT, and P450 (Chambers et al, 2011;Zhao and Pickering, 2011;Krasniak et al, 2014), yet very few SNPs have been experimentally associated directly with acetaminophen-induced hepatotoxicity (Ueshima et al, 1996;Court et al, 2013Court et al, , 2014. Genomewide association studies (GWAS) provide a powerful tool to scan for SNPs that associate with a disease phenotype, such as hepatotoxicity.…”