Inflammation is an evolutionary process that allows survival against acute infection or injury. Inflammation is also a pathophysiological condition shared by numerous chronic diseases. In addition, ...inflammation modulates important drug-metabolizing enzymes and transporters (DMETs), thus contributing to intra- and interindividual variability of drug exposure. A better knowledge of the impact of inflammation on drug metabolism and its related clinical consequences would help to personalize drug treatment.
Here, we summarize the kinetics of inflammatory mediators and the underlying transcriptional and post-transcriptional mechanisms by which they contribute to the inhibition of important DMETs. We also present an updated overview of the effect of inflammation on the pharmacokinetic parameters of most of the drugs that are DMET substrates, for which therapeutic drug monitoring is recommended. Furthermore, we provide opinions on how to integrate the inflammatory status into pharmacogenetics, therapeutic drug monitoring, and population pharmacokinetic strategies to improve the personalization of drug treatment for each patient.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Developmental Changes in Pharmacokinetics and Pharmacodynamics den Anker, John; Reed, Michael D.; Allegaert, Karel ...
Journal of clinical pharmacology,
October 2018, 2018-October, 2018-Oct, 2018-10-00, 20181001, Volume:
58, Issue:
S10
Journal Article
Peer reviewed
Open access
Effective drug therapy to optimally influence disease requires an understanding of a drug's pharmacokinetic, pharmacodynamic, and pharmacogenomic interrelationships. In pediatrics, age is a continuum ...that can and does add variability in drug disposition and effect. This article addresses the many important factors that influence drug disposition and effect relative to age. What is known about the influence of maturation on the processes of drug absorption, distribution, metabolism, excretion, and drug receptor dynamics are outlined. Our state of understanding of many of these factors remains in flux, however, and only with additional study will we be able to better anticipate and model drug‐response relationships across the age continuum. Being able to continuously improve our care of the ill pediatric patient while simultaneously being able to accurately determine the utility of new drugs and chemical entities in this population requires our enhanced understanding of these disposition characteristics.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Drugs and hepatic transporters: A review Jetter, Alexander; Kullak-Ublick, Gerd A.
Pharmacological research,
April 2020, 2020-04-00, Volume:
154
Journal Article
Peer reviewed
Open access
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The liver is the primary organ for the metabolic degradation of xenobiotics. Transmembrane transport proteins from the ABC and the SLC families mediate the uptake of endogenous ...compounds and xenobiotics into the hepatocyte as well as their elimination from the cells. Multiple processes are involved. The uptake of xenobiotics in hepatocytes is mediated by organic anion transporting polypeptides (OATPs) and by organic anion and cation transporters (OATs and OCTs). The elimination of drugs and metabolites from the liver cell back to the bloodstream is accomplished mainly by multidrug resistance-associated protein 3 (MRP3) and MRP4, while the elimination towards the biliary canaliculi is mediated by several different transporters (MRP2, BCRP, MDR1 and MATE1). Since bile acids and their salts are toxic detergents for hepatocytes, they have to be eliminated efficiently. This task is accomplished by the bile salt export pump BSEP. Two further transporters, MDR3 and ATP8B1 are involved in the proper constitution of bile. All these transporters can be influenced, mainly inhibited by a number of drugs, but also by metabolites from endogenous compounds such as estrogens. Additionally, rare monogenetic diseases exist which can be explained by absence of function or dysfunction of specific hepatic transporters, such as progressive familial intrahepatic cholestasis type 2 by genetic modifications in BSEP that lead to a loss of transporter function. Functional impairment of other transporters by genetics or by drugs also leads to liver injury, a potentially life-threatening disease that is still not fully understood. Hence, the interplay between drugs and hepatic transporters is multiple, and the knowledge of this interplay helps in understanding the etiology and molecular mechanisms behind some forms of (drug-induced) liver injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Drug Metabolism in the Liver Almazroo, Omar Abdulhameed; Miah, Mohammad Kowser; Venkataramanan, Raman
Clinics in liver disease,
02/2017, Volume:
21, Issue:
1
Journal Article
Peer reviewed
Metabolism is a biotransformation process, where endogenous and exogenous compounds are converted to more polar products to facilitate their elimination from the body. The process of metabolism is ...divided into 3 phases. Phase I metabolism involves functionalization reactions. Phase II drug metabolism is a conjugation reaction. Phase III refers to transporter-mediated elimination of drug and/or metabolites from body normally via liver, gut, kidney, or lung. This review presents basic information on drug-metabolizing enzymes and potential factors that might affect the metabolic capacities of the enzyme or alter drug response or drug-mediated toxicities.
COVID-19 is announced as a global pandemic in 2020. Its mortality and morbidity rate are rapidly increasing, with limited medications. The emergent outbreak of COVID-19 prompted by severe acute ...respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps spreading. In this infection, a patient's immune response plays pivotal role in the pathogenesis. This inflammatory factor was shown by its mediators that, in severe cases, reach the cytokine at peaks. Hyperinflammatory state may sparks significant imbalances in transporters and drug metabolic machinery, and subsequent alteration of drug pharmacokinetics may result in unexpected therapeutic response. The present scenario has accounted for the requirement for therapeutic opportunities to relive and overcome this pandemic. Despite the diminishing developments of COVID-19, there is no drug still approved to have significant effects with no side effect on the treatment for COVID-19 patients. Based on the evidence, many antiviral and anti-inflammatory drugs have been authorized by the Food and Drug Administration (FDA) to treat the COVID-19 patients even though not knowing the possible drug-drug interactions (DDI). Remdesivir, favipiravir, and molnupiravir are deemed the most hopeful antiviral agents by improving infected patient’s health. Dexamethasone is the first known steroid medicine that saved the lives of seriously ill patients. Some oligopeptides and proteins have also been using. The current review summarizes medication updates to treat COVID-19 patients in an inflammatory state and their interaction with drug transporters and drug-metabolizing enzymes. It gives an opinion on the potential DDI that may permit the individualization of these drugs, thereby enhancing the safety and efficacy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Preincubation with inhibitor in organic anion transporting polypeptide (OATP) in vitro assays may increase the inhibition potency of inhibitors compared to conventional inhibition assays with only ...short inhibitor coincubation with substrate. The decrease in IC50 may affect prediction of drug-drug interactions (DDI) involving these transporters and inhibitors. Only few drugs, however, have been assessed for the preincubation-dependent inhibition of the OATP2B1 transporter. Therefore, we studied the effect of preincubation on OATP2B1 inhibition with five known OATP2B1 inhibitors (atorvastatin, erlotinib, ezetimibe, ticagrelor and simeprevir) in HEK293 cells transiently overexpressing OATP2B1. IC50 values were determined with and without inhibitor preincubation for 20 min with three different OATP2B1 substrates (dibromofluorescein, DBF; 5-carboxyfluorescein, 5-CF; estrone sulfate). Atorvastatin, ezetimibe, and simeprevir displayed more than 2-fold lower IC50 values after preincubation with at least one of the tested substrates. Altogether, 4 out of 15 inhibitor/substrate combinations exhibited more than 2-fold potentiation of IC50 after inhibitor preincubation. In addition, preincubation by itself, without inhibitor present with the substrate, resulted in more than 50% inhibition of OATP2B1-mediated uptake of DBF and/or 5-CF by atorvastatin, ticagrelor and simeprevir. Thus, erlotinib was the only inhibitor with no indication of potentiation of inhibition by preincubation with any of the tested substrates. In conclusion, preincubation resulted in inhibitor- and substrate-dependent inhibition of OATP2B1. These results support the conclusion that to reduce the risk of false negative DDI prediction, preincubation should be considered also in OATP2B1 inhibition assays.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Medications are a relatively common cause of acute kidney injury (AKI), especially in hospitalized patients who are exposed to numerous agents. Drug-related acute tubular/tubulointerstitial injury is ...the most common cause of AKI associated with these agents. Toxic effects of drugs and their renal handling often lead to various forms of AKI.
The inherent nephrotoxicity of drugs and their transport and metabolism by the kidneys play an important role in the occurrence of acute tubular injury. Apical transport of the aminoglycosides by endocytosis and apical pinocytosis of filtered hydroxyethyl starch into cells lead to acute tubular dysfunction. Transport of tenofovir and cisplatin by organic anion and cation transporters in the basolateral surface of the proximal tubule, respectively, are associated with intracellular drug accumulation and injury. Intratubular deposition of drug crystals with associated AKI occurs with several drugs, in particular the anticancer agent methotrexate. A potentially new mechanism of drug-induced AKI was described with vancomycin - acute vancomycin-related cast nephropathy. Immune-mediated acute tubulointerstitial injury is another cause of drug-induced AKI, as seen with immune checkpoint inhibitors.
Drugs lead to AKI through mechanisms that involve their inherent toxicity as well as their transport and handling by the kidneys.
Selective serotonin reuptake inhibitors (SSRIs) are indicated for a variety of psychiatric conditions which may require treatment during pregnancy. Knowledge of appropriate SSRI dosages that maintain ...maternal therapeutic benefit and minimize fetal risk are needed. Assessment of fetal exposure to drugs is challenging since sampling is often limited to a single concentration from the umbilical cord at delivery. Physiologically based pharmacokinetic (PBPK) modelling provides a non-invasive approach to quantify exposure in pregnancy.
We incorporated sertraline clearances mediated by passive diffusion, placental efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) into our previously published pregnancy PBPK model for sertraline. Simulations were performed for various sertraline doses (25-200 mg) at 40 weeks gestational age to predict the minimum (C
), maximum (C
) and average (C
) sertraline maternal and fetal plasma concentrations and evaluated them against observed maternal and cord concentrations obtained at delivery from five clinical studies.
The accuracy of the PBPK predictions as indicated by the average fold error (AFE) value for C
, C
and C
for maternal plasma sertraline concentrations at delivery was 1.7, 1.2 and 1.4, respectively. The AFE for the C
, C
and C
for cord blood sertraline concentration at delivery was 1.2, 1 and 1.1, respectively. The AFE for cord-maternal sertraline concentration ratio at delivery for C
, C
and C
was 0.7, 0.9 and 0.8, respectively.
The PBPK model we developed may serve as a guide for maternal sertraline dose adjustment during pregnancy considering changes in exposures for both mother and fetus.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Cancer drug resistance continues to be a major impediment in medical oncology. Clinically, resistance can arise prior to or as a result of cancer therapy. In this review, we discuss different ...mechanisms adapted by cancerous cells to resist treatment, including alteration in drug transport and metabolism, mutation and amplification of drug targets, as well as genetic rewiring which can lead to impaired apoptosis. Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. Making the problem even more challenging, some of these resistance pathways lead to multidrug resistance, generating an even more difficult clinical problem to overcome. We provide examples of these mechanisms and some insights into how understanding these processes can influence the next generation of cancer therapies.
The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, ...pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual’s particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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