Age-related modifications in CYP-dependent drug metabolism: role of stress

Abstract

Accumulating clinical evidence indicates extensive inter-individual variations in the effectiveness and adverse effects of standard treatment protocols, which are largely attributed to the multifactorial regulation of the hepatic CYP-dependent drug metabolism that is connected with either transcriptional or post-translational modifications. Age and stress belong to the most important factors in CYP gene regulation. Alterations in neuroendocrine responses to stress, which are associated with modified hypothalamo-pituitary-adrenal axis function, usually accompany ageing. In this light, ageing followed by a decline of the functional integrity of organs, including liver, a failure in preserving homeostasis under stress, increased morbidity and susceptibility to stress, among others, holds a determinant role in the CYP-catalyzed drug metabolism and thus, in the outcome and toxicity of pharmacotherapy. Modifications in the drug metabolizing capacity of the liver with age have been reported and in particular, a decline in the activity of the main CYP isoforms in male senescent rats, indicating decreased metabolism and higher levels of the drug-substrates in their blood. These factors along with the restricted experience in the use of the most medicines in childhood and elderly, could explain at an extent the inter-individual variability in drug efficacy and toxicity outcomes, and underscore the necessity of designing the treatment protocols, accordingly.

Changes in the innate immune response to SARS-CoV-2 with advancing age in humans

“…We also previously observed this and have shown that PTEN signaling is increased in aging and inhibits TLR responses [ 16 ]. Several pathways related to the degradation of sugars, melatonin, etc., that involve cytochrome P450 proteins were downregulated with age, which is in keeping with the age-associated decrease in drug metabolism reported in previous studies [ 70 ].…”

Risk of stress cardiomyopathy associated with selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors: A real-world pharmacovigilance analysis

“…Some susceptibility manifestations might result from the variations in cytochrome P450 enzyme activity due to genetic polymorphisms of CYP genes (Kekic, 2023). Cytochrome P450 isoenzymes were the main determinants of the pharmacokinetic properties of antidepressant drugs (Konstandi and Johnson, 2023). Piatkov et al reported that the response to uoxetine might vary among individuals even at therapeutic dosage because of the genetic polymorphisms of the isoenzymes encoding drug metabolism (Irina Piatkov et al, 2017),.…”

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

“…Despite evaluation of drug posology selection, there is variation among individuals in drug response as a result of many different parameters associated with different factors including genomic [16][17][18][19][20], immunological [20,21], pharmacological [22,23] and toxicological variations [24,25], as well as interactions with drugs, dietary substances, etc. Similarly, there are also differences among individuals in drug response as a result of many other limitations such as underlying disease pathological complications, variations in organ functioning, idiosyncratic reactions, accessibility to effective drug posology due to high cost and other variations [22][23][24][25][26].…”