Interaction of Remdesivir with Clinically Relevant Hepatic Drug Uptake Transporters.
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ABSTRACT:
SUBMITTER: Nies AT
PROVIDER: S-EPMC7999182 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Renal drug transporters such as the organic cation transporters (OCTs), organic anion transporters (OATs) and multidrug resistance proteins (MRPs) play an important role in the tubular secretion of many drugs influencing their efficacy and safety. However, only little is known about the distinct protein abundance of these transporters in human kidneys, and about the impact of age and gender as potential factors of inter-subject variability in their expression and function. The aim of this study was to determine the protein abundance of MDR1, MRP1-4, BCRP, OAT1-3, OCT2-3, MATE1, PEPT1/2, and ORCTL2 by liquid chromatography-tandem mass spectrometry-based targeted proteomics in a set of 36 human cortex kidney samples (20 males, 16 females; median age 53 and 55 years, respectively). OAT1 and 3, OCT2 and ORCTL2 were found to be most abundant renal SLC transporters while MDR1, MRP1 and MRP4 were the dominating ABC transporters. Only the expression levels of MDR1 and ORCTL2 were significantly higher abundant in older donors. Moreover, we found several significant correlations between different transporters, which may indicate their functional interplay in renal vectorial transport processes. Our data may contribute to a better understanding of the molecular processes determining renal excretion of drugs.
| S-EPMC6862022 | biostudies-literature
Project description:Purpose: The combination therapy of rosuvastatin (RSV) and the platelet inhibitor clopidogrel (CP) is widely accepted in the management of cardiovascular diseases. The objective of the present study was to identify the mechanism of RSV-CP DDI and evaluate the risk of hepatotoxicity associated with the concomitant use of CP. Methods: We first studied the effect of CP and its major circulating metabolite, carboxylic acid metabolite (CPC), on RSV transport by overexpressing cells and membrane vesicles. Second, we investigated whether a rat model could replicate this DDI and then be used to conduct mechanistic studies and assess the risk of hepatotoxicity. Then, cytotoxicity assay in hepatocytes, biochemical examination, and histopathology were performed to measure the magnitude of liver injury in the presence and absence of DDI. Results: CP inhibited OATP1B1-mediated transport of RSV with an IC50 value of 27.39 μM. CP and CPC inhibited BCRP-mediated RSV transport with IC50 values of <0.001 and 5.96 μM, respectively. The CP cocktail (0.001 μM CP plus 2 μM CPC) significantly inhibited BCRP-mediated transport of RSV by 26.28%. Multiple p.o. doses of CP significantly increased intravenous RSV plasma AUC0-infinity by 76.29% and decreased intravenous RSV CL by 42.62%. Similarly, multiple p.o. doses of CP significantly increased p.o. RSV plasma AUC0-infinity by 87.48% and decreased p.o. RSV CL by 43.27%. CP had no effect on cell viability, while RSV exhibited dose-dependent cytotoxicity after 96 h incubation. Co-incubation of 100 μM CP and RSV for 96 h significantly increased intracellular concentrations and cell-to-medium concentration ratios of RSV and reduced hepatocyte viability. Histological evaluation of liver specimens showed patterns of drug-induced liver injury. Cholestasis was found in rats in the presence of DDI. Conclusion: CP is not a clinically relevant inhibitor for OATP1B1 and OATP1B3. The primary mechanism of RSV-CP DDI can be attributed to the inhibition of intestinal BCRP by CP combined with the inhibition of hepatic BCRP by CPC. The latter is likely to be more clinically relevant and be a contributing factor for increased hepatotoxicity in the presence of DDI.
| S-EPMC8504577 | biostudies-literature
Project description:In the field of pharmacogenetics, we currently have a few markers to guide physicians as to the best course of therapy for patients. For the most part, these genetic variants are within a drug metabolizing enzyme that has a large effect on the degree or rate at which a drug is converted to its metabolites. For many drugs, response and toxicity are multi-genic traits and understanding relationships between a patient's genetic variation in drug metabolizing enzymes and the efficacy and/or toxicity of a medication offers the potential to optimize therapies. This review will focus on variants in drug metabolizing enzymes with predictable and relatively large impacts on drug efficacy and/or toxicity; some of these drug/gene variant pairs have impacted drug labels by the United States Food and Drug Administration. The challenges in identifying genetic markers and implementing clinical changes based on known markers will be discussed. In addition, the impact of next generation sequencing in identifying rare variants will be addressed.
| S-EPMC3110519 | biostudies-literature
Project description:BackgroundAttention-deficit/hyperactivity disorder is a psychiatric disorder that starts in childhood. The mechanism of action of methylphenidate, the most common treatment for attention deficit hyperactivity disorder, is unclear. In vitro, the affinity of methylphenidate for the norepinephrine transporter (NET) is higher than that for the dopamine transporter (DAT). The goal of this study was to use positron emission tomography to measure the occupancy of brain norepinephrine transporter by methylphenidate in vivo in humans.MethodsWe used (S,S)-[¹¹C] methylreboxetine ([¹¹C]MRB) to determine the effective dose 50 (ED₅₀) of methylphenidate for NET. In a within-subject design, healthy subjects (n = 11) received oral, single-blind placebo and 2.5, 10, and 40 mg of methylphenidate 75 min before [¹¹C]MRB injection. Dynamic positron emission tomography imaging was performed for 2 hours with the High Resolution Research Tomograph. The multilinear reference tissue model with occipital cortex as the reference region was used to estimate binding potential non-displaceable (BP(ND)) in the thalamus and other NET-rich regions.ResultsBP(ND) was reduced by methylphenidate in a dose-dependent manner in thalamus and other NET-rich regions. The global ED₅₀ was estimated to be .14 mg/kg; therefore, the average clinical maintenance dose of methylphenidate (.35-.55 mg/kg) produces 70% to 80% occupancy of NET.ConclusionsFor the first time in humans, we demonstrate that oral methylphenidate significantly occupies NET at clinically relevant doses. The ED₅₀ is lower than that for DAT (.25 mg/kg), suggesting the potential relevance of NET inhibition in the therapeutic effects of methylphenidate in attention-deficit/hyperactivity disorder.
| S-EPMC3742016 | biostudies-literature
Project description:BackgroundHuman plasmacytoid dendritic cells (pDC) have a dual role as interferon-producing and antigen-presenting cells. Their relevance for allergic diseases is controversial. and the impact of pDC on allergic immune responses is poorly understood.MethodsThis in vitro study on human pDC isolated from peripheral blood was designed to compare side by side the uptake of three clinically relevant representative allergens: fluorochrome-labeled house dust mite Der p 1, Bee venom extract from Apis mellifera (Api) and the food allergen OVA analyzed flow cytometry and confocal microscopy.ResultsWe found that the internalization and its regulation by TLR9 ligation was significantly different between allergens in terms of time course and strength of uptake. Api and OVA uptake in pDC of healthy subjects was faster and reached higher levels than Der p 1 uptake. CpG ODN 2006 suppressed OVA uptake and to a lesser extent Der p 1, while Api internalization was not affected. All allergens colocalized with LAMP1 and EEA1, with Api being internalized particularly fast and reaching highest intracellular levels in pDC. Of note, we could not determine any specific differences in antigen uptake in allergic compared with healthy subjects.ConclusionsTo our knowledge this is the first study that directly compares uptake regulation of clinically relevant inhalative, injective and food allergens in pDC. Our findings may help to explain differences in the onset and severity of allergic reactions as well as in the efficiency of AIT.
| S-EPMC8597288 | biostudies-literature
Project description:G-protein-coupled receptors (GPCRs) are the largest family of integral membrane receptors with key roles in regulating signaling pathways targeted by therapeutics, but are difficult to study using existing proteomics technologies due to their complex biochemical features. To obtain a global view of GPCR-mediated signaling and to identify novel components of their pathways, we used a modified membrane yeast two-hybrid (MYTH) approach and identified interacting partners for 48 selected full-length human ligand-unoccupied GPCRs in their native membrane environment. The resulting GPCR interactome connects 686 proteins by 987 unique interactions, including 299 membrane proteins involved in a diverse range of cellular functions. To demonstrate the biological relevance of the GPCR interactome, we validated novel interactions of the GPR37, serotonin 5-HT4d, and adenosine ADORA2A receptors. Our data represent the first large-scale interactome mapping for human GPCRs and provide a valuable resource for the analysis of signaling pathways involving this druggable family of integral membrane proteins.
| S-EPMC5371730 | biostudies-literature
Project description:Fusidic acid (FA), which was approved in the 1960s in many European and Asian countries, has gained renewed interest due to its continued effectiveness against methicillin-resistant Staphylococcus aureus As rhabdomyolysis has been reported upon coadministration of FA with statins, we aimed to elucidate the underlying molecular mechanisms that contribute to FA-statin drug-drug interactions. Because of the association between rhabdomyolysis and increased exposure to statins, we investigated if cytochrome P450 (CYP) enzymes and transporters involved in the disposition of various statins are inhibited by FA. FA was found to inhibit BCRP and OATP1B1 but not P-gp. In overexpressing cell systems, FA inhibited BCRP-mediated efflux (50% inhibitory concentration [IC50], ?50 to 110 ?M) and OATP1B1-mediated uptake (IC50, ?4 to 35 ?M) of statins at clinically relevant concentrations achievable in the intestine and liver (based on a 550-mg oral dose of FA, the expected maximum theoretical gastrointestinal concentration is ?4 mM, and the maximum total or unbound concentration in the inlet to the liver was reported to be up to 223 ?M or 11 ?M, respectively, upon multiple dosing). Similarly, FA inhibited metabolism of statins in human liver microsomes (IC50, ?17 to 195 ?M). These data suggest that FA inhibits at least 3 major dispositional pathways (BCRP, OATP1B1, and CYP3A) and thus affects the clearance of several statins. We confirmed that FA is eliminated via phase 1 metabolism (primarily via CYP3A); however, there is also some phase 2 metabolism (mediated primarily by UGT1A1). Taken together, these data provide evidence for molecular mechanisms that may explain the occurrence of rhabdomyolysis when FA is administered with statins.
| S-EPMC5038258 | biostudies-other
Project description:AimsDalcetrapib, which targets cholesteryl ester transfer protein activity, is in development for prevention of cardiovascular events. Because dalcetrapib will likely be prescribed with other lipid-modifying therapies such as ezetimibe, a study was performed to investigate potential pharmacokinetic interactions between dalcetrapib and ezetimibe. Lipids changes and tolerability were secondary endpoints.MethodsCo-administration of dalcetrapib 900 mg (higher than the phase III dose) with ezetimibe was investigated in a three period, three treatment crossover study in healthy males: 7 days of dalcetrapib, 7 days of dalcetrapib plus ezetimibe, 7 days of ezetimibe alone. A full pharmacokinetic profile was performed on day 7 of each treatment.ResultsCo-administration of dalcetrapib with ezetimibe was associated with minimal changes in dalcetrapib exposure compared with dalcetrapib alone. Least squares mean ratio (LSMR) (90% confidence interval) was 93.6 (87.1, 100.7) for AUC(0,24 h) and 99.0 (85.2, 115.0) for C(max) . Ezetimibe exposure was reduced with co-administration of ezetimibe with dalcetrapib compared with ezetimibe alone: LSMR 80.3 (74.6, 86.4) for AUC(0,24 h) and 88.9 (80.9, 99.9) for C(max) for total ezetimibe. High-density lipoprotein cholesterol increases associated with co-administration of dalcetrapib with ezetimibe (+29.8%) were comparable with those with dalcetrapib alone (+25.6%), while the reduction in low-density lipoprotein cholesterol with co-administration (-35.9%) was greater than with ezetimibe alone (-20.9%). Dalcetrapib was generally well tolerated when administered alone and when co-administered with ezetimibe.ConclusionCo-administration of dalcetrapib with ezetimibe was not associated with clinically significant changes in pharmacokinetic parameters or tolerability and did not diminish the lipid effects of either drug.
| S-EPMC3014066 | biostudies-literature
Project description:This study describes early treatment drug use status and associated clinical characteristics in a diverse sample of patients entering outpatient substance abuse psychosocial counseling treatment. The goal is to more fully characterize those entering treatment with and without active use of their primary drug in order to better understand associated treatment needs and resilience factors.We examined baseline data from a NIDA Clinical Trials Network (CTN) study (Web-delivery of Treatment for Substance Use) with an all-comers sample of patients (N?=?494) entering 10 outpatient treatment centers. Patients were categorized according to self-identified primary drug of abuse (alcohol, cocaine/stimulants, opioids, marijuana) and by baseline drug use status (positive/negative) based on urine testing or self-reports of recent use (alcohol). Characteristics were examined by primary drug and early use status.Classified as drug-negative were 84%, 76%, 62%, and 33% of primary opioid, stimulant, alcohol, and marijuana users; respectively. Drug-positive versus -negative patients did not differ on demographics or rates of substance abuse/dependence diagnoses. However, those negative for active use had better physical and mental health profiles, were less likely to be using a secondary drug, and were more likely to be attending 12-step self-help meetings.Early treatment drug abstinence is common among substance users entering outpatient psychosocial counseling programs, regardless of primary abused drug. Abstinence (by negative UA) is associated with better health and mental health profiles, less secondary drug use, and more days of 12-step attendance. These data highlight differential treatment needs and resiliencies associated with early treatment drug use status.NCT01104805.
| S-EPMC4234981 | biostudies-literature
Project description:BackgroundAdverse effects (AEs) of antiepileptic drugs (AEDs) are a major impediment to optimal dosing for seizure control. Better understanding of clinical properties of AEs is a prerequisite for systematic research of their neurobiological underpinnings. This study aimed to define specific patterns of AE occurrence and determine their clinical relevance based on their association with subjective health status.MethodsTwo hundred subjects with epilepsy completed validated self-report health assessments, including the Adverse Event Profile (AEP) and Quality of Life in Epilepsy Inventory (QOLIE)-89. Factor analysis was performed on the 19 AEP items to identify distinct classes of AEs. Correlations between AE class scores and QOLIE-89 scores were evaluated. Multivariate analysis was used to assess contributions of AE class scores to QOLIE-89 scores after controlling for depression and seizure frequency. Relationships between changes in AE class scores and changes in QOLIE-89 scores were also investigated in a subgroup of 62 subjects enrolled in a randomized trial.ResultsThe mean number of AEs per subject was 6.5. AEs were segregated into five classes: Cognition/Coordination, Mood/Emotion, Sleep, Weight/Cephalgia, and Tegument/Mucosa. Higher scores in each AE class were associated with lower QOLIE-89 scores. Cognition/Coordination scores were the strongest predictor of QOLIE-89 scores. Improvements in Cognition/Coordination, Mood/Emotion, and Tegument/Mucosa scores were associated with improvements in QOLIE-89 scores. Improved Cognition/Coordination was the only predictor of improved QOLIE-89.ConclusionAdverse effects (AEs) of antiepileptic drugs can be classified in five biologically plausible factors. When specific classes of AEs are identified and attempts are made to reduce them, quality of life is significantly improved.
| S-EPMC2677485 | biostudies-literature