Introduction of Drug Metabolism and Overview of Disease Effect on Drug Metabolism

Sane, Ramola; Sinz, Michael

doi:10.1016/b978-0-12-802949-7.00001-8

Cited by 7 publications

(12 citation statements)

References 62 publications

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“…In fact, antipsychotic drugs have been associated with immunoregulatory properties. Altogether, these factors challenge the prediction of the dose-response relationship of psychotropic drugs and highlight the necessity of regular TDM in clinical routine [41], as the influence of both factors on drug levels is often insufficiently addressed by pharmaceutical companies during drug development [27]. If these factors do find consideration, analyses are often based on in vitro models with limited relevance for human metabolism [15].…”

Section: Enzymes Involved In Drugmentioning

confidence: 99%

“…Binding to TLRs results in an activation of the nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB), a central transcription factor family involved in pro-inflammatory cytokine production [154][155][156][157]. This cascade (also named acute-phase reaction, APR) not only serves in the recruitment of peripheral immune cells to the site of tissue damage [158][159][160] enabling, for example, enhanced phagocytosis and thus tissue repair [161][162][163], but also leads to changes in drug metabolism [27,31,41,157].…”

Section: Physiology Of Inflammationmentioning

confidence: 99%

“…IL-6 was further shown to suppress CYP1A2, CYP2B6, and CYP3A4 mRNA levels [178] and to be associated with inhibited CYP3A4, CYP1A2, and CYP2C19 functioning (but not CYP2E or CYP2D6) in patients with cancer, congestive heart failure, or post-surgery [41,[179][180][181]. Administration of tocilizumab (an anti-IL-6 receptor antibody used in the treatment of rheumatoid arthritis), increased the activity of CYP3A4 and thus simvastatin clearance [182]; however, no effect was prevalent regarding CYP2C19 and CYP2D6 as measured by the elimination of omeprazole and dextromethorphan, respectively [27,183]. Regarding IL-1, in vitro studies demonstrate a marked downregulation of CYP2C8 and CYP3A4 mRNA, but not of CYP2C9 or CYP2C19 [184].…”

Section: Effects Of Inflammation On Cyp Isoenzymesmentioning

confidence: 99%

“…However, other relevant proteins must also be considered: uridine diphosphate-glucuronosyltransferases (UDP-GTs), sulfotransferases, glutathione S-transferases (GSTs), N-acyltransferases, and methyltransferases. All of these enzymes are categorized as so-called phase II conjugative enzymes, as they add particular moieties to drugs to modulate their lipophilic/hydrophilic properties [27]. As in the case of inflammatory substances other than IL-1, IL-6, and TNFα, phase II enzymes have received much less attention than CYP enzymes.…”

Section: Effect Of Inflammation On Other Drug-metabolizing Proteins and Transportersmentioning

confidence: 99%

“…In this context, inflammation and smoking behavior have been reported to influence activity of cytochrome-P450 (CYP) isoenzymes (the humans' main metabolizing system for xenobiotic substances), efficacy of drug transporters, and drug binding to plasma proteins (see Sections 2.2 and 3.2). Inhibition or induction of drug metabolism has diverse consequences depending, for instance, on a drug's properties [27], pharmacogenetics (i.e., single nucleotide polymorphisms (SNPs) affecting the genes encoding CYP enzymes) [28][29][30][31], the simultaneous intake of other substances, or diet [32][33][34]. Changes in LADME of antipsychotic drugs in the context of smoking and inflammation are particularly relevant, as inflammation-related ADRs such as hepatitis, pancreatitis, and myocarditis [35] have been reported after use of, e.g., clozapine [36].…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

et al. 2021

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Both inflammation and smoking can influence a drug’s pharmacokinetic properties, i.e., its liberation, absorption, distribution, metabolism, and elimination. Depending on, e.g., pharmacogenetics, these changes may alter treatment response or cause serious adverse drug reactions and are thus of clinical relevance. Antipsychotic drugs, used in the treatment of psychosis and schizophrenia, should be closely monitored due to multiple factors (e.g., the narrow therapeutic window of certain psychotropic drugs, the chronicity of most mental illnesses, and the common occurrence of polypharmacotherapy in psychiatry). Therapeutic drug monitoring (TDM) aids with drug titration by enabling the quantification of patients’ drug levels. Recommendations on the use of TDM during treatment with psychotropic drugs are presented in the Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology; however, data on antipsychotic drug levels during inflammation or after changes in smoking behavior—both clinically relevant in psychiatry—that can aid clinical decision making are sparse. The following narrative review provides an overview of relevant literature regarding TDM in psychiatry, particularly in the context of second- and third-generation antipsychotic drugs, inflammation, and smoking behavior. It aims to spread awareness regarding TDM (most pronouncedly of clozapine and olanzapine) as a tool to optimize drug safety and provide patient-tailored treatment.

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Section: Enzymes Involved In Drugmentioning

confidence: 99%

Section: Physiology Of Inflammationmentioning

confidence: 99%

Section: Effects Of Inflammation On Cyp Isoenzymesmentioning

confidence: 99%

Section: Effect Of Inflammation On Other Drug-metabolizing Proteins and Transportersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

et al. 2021

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The biomedical potential of tardigrade proteins: A review

Kasianchuk¹,

Rzymski²,

Kaczmarek³

2023

Biomedicine & Pharmacotherapy

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Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics

et al. 2022

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Non-clinical models to study metabolism including animal models and cell assays are often limited in terms of species translatability and predictability of human biology. This field urgently requires a push towards more physiologically accurate recapitulations of drug interactions and disease progression in the body. Organ-on-chip systems, specifically multi-organ chips (MOCs), are an emerging technology that is well suited to providing a species-specific platform to study the various types of metabolism (glucose, lipid, protein and drug) by recreating organ-level function. This review provides a resource for scientists aiming to study human metabolism by providing an overview of MOCs recapitulating aspects of metabolism, by addressing the technical aspects of MOC development and by providing guidelines for correlation with in silico models. The current state and challenges are presented for two application areas: (i) disease modelling and (ii) pharmacokinetics/pharmacodynamics. Additionally, the guidelines to integrate the MOC data into in silico models could strengthen the predictive power of the technology. Finally, the translational aspects of metabolizing MOCs are addressed, including adoption for personalized medicine and prospects for the clinic. Predictive MOCs could enable a significantly reduced dependence on animal models and open doors towards economical non-clinical testing and understanding of disease mechanisms.

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Introduction of Drug Metabolism and Overview of Disease Effect on Drug Metabolism

Cited by 7 publications

References 62 publications

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

The biomedical potential of tardigrade proteins: A review

Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics

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