Genetically Determined Polymorphisms in Drug Metabolism

1992 ◽  
Vol 5 (6) ◽  
pp. 317-336
Author(s):  
Y.W. Francis Lam ◽  
Milton V. Marshall
Keyword(s):  
Drug Metabolism ◽  
Metabolic Pathway ◽  
Drug Response ◽  
Adverse Reactions ◽  
Drug Disposition ◽  
Poor Metabolizer ◽  
Extensive Metabolizer ◽  
Different Types ◽  
Metabolizing Enzyme ◽  
Genetically Determined

Many factors can influence the metabolism and disposition of drugs. Genetically determined differences in an individual's capacity to metabolize drugs are known causes of interindividual and interethnic variabilities in drug disposition and response. In general, a poor metabolizer for a specific metabolic pathway would likely develop adverse effects, and an extensive metabolizer for the same metabolic pathway might have less than optimal response. Although there are different types of polymorphism in drug metabolism, polymorphisms in debrisoquine-type oxidation, S-mephenytoin oxidation, and N-acetylation have been the most extensively studied. This article will present the basic concepts of pharmacogenetics, review the major types of metabolic polymorphisms, outline ways to determine phenotyping and genotyping differences in metabolizing enzyme activities, and discuss how these differences relate to drug metabolism, response, and toxicity. When evaluating drug response and adverse reactions in individual patients, an awareness of genetic differences in metabolic capacities would help contribute to optimization in drug therapy.

scholarly journals Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification

2021 ◽  
Author(s):  
Lawrence Howell ◽  
Rosalind E. Jenkins ◽  
Stephen Lynch ◽  
Carrie Duckworth ◽  
B. Kevin Park ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Rna Polymerase Ii ◽  
Liver Tissue ◽  
Drug Disposition ◽  
Multiple Drug ◽  
Proteomic Profiling ◽  
Cytochrome P450 3A ◽  
Drug Induced

AbstractHepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10–1000 µM) and irinotecan (1–100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.

Fundamentals of drug metabolism and drug disposition

1973 ◽  
Vol 2 ◽  
pp. 126
Author(s):  
Robert Brundin ◽  
Sten Orrenius
Keyword(s):  
Drug Metabolism ◽  
Drug Disposition

scholarly journals Genetic variations in the drug metabolizing enzyme, CYP2E1, among various ethnic populations of Pakistan

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9721
Author(s):  
Sagheer Ahmed ◽  
Nadeem Altaf ◽  
Mahnoor Ejaz ◽  
Zaira Zulfiqar ◽  
Kholood Janjua ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Adverse Effects ◽  
Drug Response ◽  
Variable Response ◽  
Healthy Human ◽  
Pakistani Population ◽  
Drug Metabolizing Enzyme ◽  
Different Populations ◽  
Metabolizing Enzyme ◽  
Low Activity

Genetic polymorphism in cytochrome P450 (CYP) monooxygenase genes is an important source of interindividual variability of drug response. CYP enzyme activities may change as a result of such polymorphisms which then, may affect drug metabolism. This would result in a change in the severity and frequency of adverse effects in addition to the non-responder phenomenon. CYP2E1, a member of CYP superfamily, affects the metabolism of several clinically important drugs such as halothane, paracetamol, etc. Genetic variation in CYP2E1 is known to cause significant inter-individual differences in drug response and adverse effects. The degree of genetic variation is found to be different in different populations around the world. The frequencies of two important polymorphisms in the CYP2E1*7C, NC_000010.10:g.135340548A>G (rs2070672) and CYP2E1, NC_000010.10:g.135339244G>C (rs3813865), are not known in the Pakistani population. In the present investigation, 636 healthy human volunteers were screened for these two single nucleotide polymorphism. Our results indicate that about 18% (rs2070672) and 28% (rs3813865) of the Pakistani population has a genotype containing at least one low activity allele. A significant interethnic variation in the frequencies of both the polymorphisms was observed. These results suggest that pharmacogenetics screening for low activity genotypes would be a helpful tool for clinicians when they prescribe medications metabolized by CYP2E1, as a significant fraction of the Pakistani population is expected to have a variable response to these drugs.

Pharmacology and Drug Therapy in Critically Ill Elderly Patients

1992 ◽  
Vol 3 (1) ◽  
pp. 137-148 ◽  
Author(s):  
Mary K. Walker
Keyword(s):  
Older Adults ◽  
Critical Care ◽  
Drug Therapy ◽  
Drug Metabolism ◽  
Elderly Patients ◽  
Treatment Modality ◽  
Drug Disposition ◽  
Structure And Function ◽  
Living Things ◽  
And Function

Aging is a complex, normal, and inevitable process affecting all living things. The physiologic changes of aging, by definition, are postmaturational, occurring after adult maturity is achieved. Changes with aging are primary, irreversible, and progressive. While the processes of aging are neither pathology nor disease, they present important changes in structure and function that alter drug disposition, metabolic rate, and excretion. These changes present special challenges to clinicians in critical care settings for whom pharmacotherapy is a common treatment modality. This article explores the physiologic changes associated with aging and the implications of these changes for management of critically compromised elders. Drug metabolism, distribution, utilization, and excretion in older adults are examined

Incidence of Roentgen Contrast Medium Reactions after Intravenous Injection in Pre-Registration Trials and Post-Marketing Surveillances

1993 ◽  
Vol 34 (3) ◽  
pp. 210-213 ◽  
Author(s):  
E. Andrew ◽  
T. Haider
Keyword(s):  
Relative Risk ◽  
Adverse Drug Reactions ◽  
Odds Ratio ◽  
Adverse Reactions ◽  
Drug Reactions ◽  
Feasible Method ◽  
Ionic Contrast ◽  
Different Types ◽  
Post Marketing ◽  
The Absolute

The relative risk of adverse drug reactions of ionic versus non-ionic contrast media injected i.v. were compared for different types of trials using odds-ratio. The absolute and relative risk found in large post-marketing trials were compared with that found in the iohexol pre-registration trials. The absolute risks were 2 to 10 times higher in the pre-registration trials compared to the post-marketing surveillances. The relative risk for all adverse drug reactions was 3 to 6 times higher for ionic vs. non-ionic media and independent of pre- or post-registration studies. The odds-ratio seems to be a feasible method of comparing the relative risk of adverse reactions in various trials.

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