Experimental Models of Drug Metabolism and Disposition

Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs—primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes—and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response.

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Cytochromes P450 and experimental models of drug metabolism

Journal of Cellular and Molecular Medicine ◽

10.1111/j.1582-4934.2002.tb00186.x ◽

2002 ◽

Vol 6 (2) ◽

pp. 189-198 ◽

Cited By ~ 196

Author(s):

R. Zuber ◽

Eva Anzenbacherová ◽

P. Anzenbacher

Keyword(s):

Drug Metabolism ◽

Cytochromes P450 ◽

Experimental Models

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Cross-species analysis of hepatic cytochrome P450 and transport protein expression

Archives of Toxicology ◽

10.1007/s00204-020-02939-4 ◽

2020 ◽

Author(s):

Helen Hammer ◽

Felix Schmidt ◽

Philip Marx-Stoelting ◽

Oliver Pötz ◽

Albert Braeuning

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism ◽

Decisive Role ◽

Pregnane X Receptor ◽

Test System ◽

Experimental Models ◽

Comprehensive Overview ◽

Cyp Enzymes

Abstract Most drugs and xenobiotics are metabolized in the liver. Amongst others, different cytochrome P450 (CYP) enzymes catalyze the metabolic conversion of foreign compounds, and various transport proteins are engaged in the excretion of metabolites from the hepatocytes. Inter-species and inter-individual differences in the hepatic levels and activities of drug-metabolizing enzymes and transporters result from genetic as well as from environmental factors, and play a decisive role in determining the pharmacokinetic properties of a compound in a given test system. To allow for a meaningful comparison of results from metabolism studies, it is, therefore, of utmost importance to know about the specific metabolic properties of the test systems, especially about the levels of metabolic enzymes such as the CYPs. Using a targeted proteomics approach, we, therefore, compared the hepatic levels of important CYP enzymes and transporters in different experimental systems in vivo and in vitro, namely Wistar rats, C57/Bl6 mice, mice humanized for the two xeno-sensing receptors PXR (pregnane-X-receptor) and CAR (constitutive androstane receptor), mice with human hepatocyte-repopulated livers, human HepaRG hepatocarcinoma cells, primary human hepatocytes, and human liver biopsies. In addition, the effects of xenobiotic inducers of drug metabolism on CYP enzymes and transporters were analyzed in selected systems. This study for the first time presents a comprehensive overview of similarities and differences in important drug metabolism-related proteins among the different experimental models.

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Preclinical experimental models of drug metabolism and disposition in drug discovery and development

Acta Pharmaceutica Sinica B ◽

10.1016/j.apsb.2012.10.004 ◽

2012 ◽

Vol 2 (6) ◽

pp. 549-561 ◽

Cited By ~ 142

Author(s):

Donglu Zhang ◽

Gang Luo ◽

Xinxin Ding ◽

Chuang Lu

Keyword(s):

Drug Discovery ◽

Drug Metabolism ◽

Experimental Models ◽

Drug Discovery And Development

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ACE2 as therapeutic agent

Clinical Science ◽

10.1042/cs20200570 ◽

2020 ◽

Vol 134 (19) ◽

pp. 2581-2595

Author(s):

Qiuhong Li ◽

Maria B. Grant ◽

Elaine M. Richards ◽

Mohan K. Raizada

Keyword(s):

Therapeutic Agent ◽

Renin Angiotensin System ◽

Peptide Hormone ◽

Experimental Models ◽

Electrolyte Balance ◽

Ang Ii ◽

Angiotensin Converting Enzyme 2 ◽

Beneficial Effects ◽

Overwhelming Evidence ◽

Future Challenges

Abstract The angiotensin-converting enzyme 2 (ACE2) has emerged as a critical regulator of the renin–angiotensin system (RAS), which plays important roles in cardiovascular homeostasis by regulating vascular tone, fluid and electrolyte balance. ACE2 functions as a carboxymonopeptidase hydrolyzing the cleavage of a single C-terminal residue from Angiotensin-II (Ang-II), the key peptide hormone of RAS, to form Angiotensin-(1-7) (Ang-(1-7)), which binds to the G-protein–coupled Mas receptor and activates signaling pathways that counteract the pathways activated by Ang-II. ACE2 is expressed in a variety of tissues and overwhelming evidence substantiates the beneficial effects of enhancing ACE2/Ang-(1-7)/Mas axis under many pathological conditions in these tissues in experimental models. This review will provide a succinct overview on current strategies to enhance ACE2 as therapeutic agent, and discuss limitations and future challenges. ACE2 also has other functions, such as acting as a co-factor for amino acid transport and being exploited by the severe acute respiratory syndrome coronaviruses (SARS-CoVs) as cellular entry receptor, the implications of these functions in development of ACE2-based therapeutics will also be discussed.

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