scholarly journals 2500. Fostemsavir Drug–Drug Interaction Profile, an Attachment Inhibitor and Oral Prodrug of Temsavir, for Heavily Treatment Experienced HIV-1-Infected Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S867-S867 ◽  
Author(s):  
Katy P Moore ◽  
A Savannah Mageau ◽  
Mindy Magee ◽  
Peter D Gorycki ◽  
Peter Ackerman ◽  
...  
Keyword(s):  
Organic Anion ◽  
Viral Envelope ◽  
Organic Anion Transporter ◽  
Uridine Diphosphate ◽  
Cancer Resistance ◽  
Viral Attachment ◽  
Transporter Protein ◽  
Anion Transporter ◽  
The Impact ◽  
Hiv 1

Abstract Background Fostemsavir (FTR) is a first-in-class attachment inhibitor being evaluated in heavily treatment-experienced (HTE) HIV-1-infected patients. Active temsavir (TMR) binds to viral envelope glycoprotein 120 and prevents viral attachment and entry into host CD4+ T cells. TMR is primarily metabolized by esterase-mediated hydrolysis with contributions from cytochrome P450 (CYP) 3A4. TMR does not inhibit/induce major CYP or uridine diphosphate glucuronosyltransferase (UGT) enzymes and is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate. TMR and/or its metabolites inhibit BCRP and organic anion transporter protein 1B1/3 (OATP1B1/3). FTR DDI profile informs coadministration with antiretrovirals (ARV) and other therapeutic classes. Methods DDI data from 13 studies were compiled to inform the impact of 17 drugs or drug combinations on TMR and the impact of TMR on 15 drugs such as ARVs, rifamycins, opioid substitutes, statins, oral contraceptives (OC), and H2-antagonsits. Results FTR with CYP3A4, P-gp, and/or BCRP inhibitors increase TMR concentrations; but, do not pose clinical concern at therapeutic dose. TMR may be administered with weak/moderate inducers with or without coadministration of CYP3A4, P-gp, and/or BCRP inhibitors such as RTV or COBI. Coadministration with strong inducers is contraindicated. FTR may be coadministered with RBT with or without a PK enhancer. However, co-administration of FTR with RIF is contraindicated. FTR can be given with drugs that increase gastric pH; famotidine did not impact TMR PK. TMR may increase concentrations of drugs that are substrates of OATP1B1/3 and BCRP; therefore, most statins require dose reduction (e.g., rosuvastatin dose is limited to ≤10 mg QD). TMR increased EE exposure 40% with no impact on NE; therefore, FTR may be coadministered with OCs containing ≤30 µg EE. TMR had no clinically meaningful impact on TDF, DRV/RTV, ATV/RTV, ATV, RTV, ETR, MET, or BUP/norBUP PK (Table 1). Conclusion FTR can be coadministered with ARVs and most common treatments used to manage HIV co-infections or comorbidities without dose adjustment of either drug except for select HMG-CoA reductase inhibitors and EE-containing OCs. Strong CYP3A inducers are contraindicated. Disclosures All authors: No reported disclosures.

scholarly journals Islatravir Is Not Expected to Be a Victim or Perpetrator of Drug-Drug Interactions via Major Drug-Metabolizing Enzymes or Transporters

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1566
Author(s):  
Kelly Bleasby ◽  
Robert Houle ◽  
Michael Hafey ◽  
Meihong Lin ◽  
Jingjing Guo ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Organic Anion Transporter ◽  
Uridine Diphosphate ◽  
Cancer Resistance ◽  
Treatment And Prevention ◽  
Anion Transporter

Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1. The potential for islatravir to interact with commonly co-prescribed medications was studied in vitro. Elimination of islatravir is expected to be balanced between adenosine deaminase–mediated metabolism and renal excretion. Islatravir did not inhibit uridine diphosphate glucuronosyltransferase 1A1 or cytochrome p450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor did it induce CYP1A2, 2B6, or 3A4. Islatravir did not inhibit hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 2, MRP3, or MRP4. Islatravir was neither a substrate nor a significant inhibitor of renal transporters organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion protein (MATE) 1, or MATE2K. Islatravir did not significantly inhibit P-glycoprotein and breast cancer resistance protein (BCRP); however, it was a substrate of BCRP, which is not expected to be of clinical significance. These findings suggest islatravir is unlikely to be the victim or perpetrator of drug-drug interactions with commonly co-prescribed medications, including statins, diuretics, anti-diabetic drugs, proton pump inhibitors, anticoagulants, benzodiazepines, and selective serotonin reuptake inhibitors.

scholarly journals In Vitro Evaluation of the Drug Interaction Potential of Doravirine

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Kelly Bleasby ◽  
Kerry L. Fillgrove ◽  
Robert Houle ◽  
Bing Lu ◽  
Jairam Palamanda ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Reversible Inhibitor ◽  
Drug Metabolizing Enzymes ◽  
Cancer Resistance ◽  
Metabolizing Enzymes ◽  
Anion Transporter ◽  
Major Drug

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 μM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.

scholarly journals Dexamethasone induces an imbalanced fetal-placental-maternal bile acid circulation: involvement of placental transporters

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Wen Huang ◽  
Jin Zhou ◽  
Juanjuan Guo ◽  
Wen Hu ◽  
Guanghui Chen ◽  
...  
Keyword(s):  
Bile Acid ◽  
Organic Anion ◽  
Maternal Serum ◽  
Farnesoid X Receptor ◽  
Organic Anion Transporter ◽  
Cancer Resistance ◽  
Rat Serum ◽  
Altered Expression ◽  
Anion Transporter ◽  
Fetal Serum

Abstract Background The use of prenatal dexamethasone remains controversial. Our recent studies found that prenatal dexamethasone exposure can induce maternal intrahepatic cholestasis and have a lasting adverse influence on bile acid (BA) metabolism in the offspring. The purpose of this study was to investigate the effects of dexamethasone on fetal-placental-maternal BA circulation during the intrauterine period, as well as its placental mechanism. Methods Clinical data and human placentas were collected and analyzed. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0.2 mg/kg per day) from gestational day 9 to 20. The metabolomic spectra of BAs in maternal and fetal rat serum were determined by LC-MS. Human and rat placentas were collected for histological and gene expression analysis. BeWo human placental cell line was treated with dexamethasone (20–500 nM). Results Human male neonates born after prenatal dexamethasone treatment showed an increased serum BA level while no significant change was observed in females. Moreover, the expression of organic anion transporter polypeptide-related protein 2B1 (OATP2B1) and breast cancer resistance protein (BCRP) in the male neonates’ placenta was decreased, while multidrug resistance-associated protein 4 (MRP4) was upregulated. In experimental rats, dexamethasone increased male but decreased female fetal serum total bile acid (TBA) level. LC-MS revealed that primary BAs were the major component that increased in both male and female fetal serum, and all kinds of BAs were significantly increased in maternal serum. The expression of Oatp2b1 and Bcrp were reduced, while Mrp4 expression was increased in the dexamethasone-treated rat placentas. Moreover, dexamethasone increased glucocorticoid receptor (GR) expression and decreased farnesoid X receptor (FXR) expression in the rat placenta. In BeWo cells, dexamethasone induced GR translocation into the nucleus; decreased FXR, OATP2B1, and BCRP expression; and increased MRP4 expression. Furthermore, GR was verified to mediate the downregulation of OATP2B1, while FXR mediated dexamethasone-altered expression of BCRP and MRP4. Conclusions By affecting placental BA transporters, dexamethasone induces an imbalanced fetal-placental-maternal BA circulation, as showed by the increase of primary BA levels in the fetal serum. This study provides an important experimental and theoretical basis for elucidating the mechanism of dexamethasone-induced alteration of maternal and fetal BA metabolism and for exploring early prevention and treatment strategies.

scholarly journals The Emerging Role of the SLCO1B3 Protein in Cancer Resistance

2019 ◽  
Vol 27 (1) ◽  
pp. 17-29 ◽  
Author(s):  
Ruipu Sun ◽  
Ying Ying ◽  
Zhimin Tang ◽  
Ting Liu ◽  
Fuli Shi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Anticancer Drugs ◽  
Organic Anion ◽  
Chemotherapy Resistance ◽  
Organic Anion Transporter ◽  
Cancer Drug ◽  
Cancer Resistance ◽  
Anticancer Chemotherapy ◽  
Anion Transporter ◽  
Transporter Family

Currently, chemotherapy is one of the mainstays of oncologic therapies. But the efficacy of chemotherapy is often limited by drug resistance and severe side effects. Consequently, it is becoming increasingly important to investigate the underlying mechanism and overcome the problem of anticancer chemotherapy resistance. The solute carrier organic anion transporter family member 1B3 (SLCO1B3), a functional transporter normally expressed in the liver, transports a variety of endogenous and exogenous compounds, including hormones and their conjugates as well as some anticancer drugs. The extrahepatic expression of SLCO1B3 has been detected in different cancer cell lines and cancer tissues. Recently, accumulating data indicates that the abnormal expression and function of SLCO1B3 are involved in resistance to anticancer drugs, such as taxanes, camptothecin and its analogs, SN-38, and Androgen Deprivation Therapy (ADT) in breast, prostate, lung, hepatic, and colorectal cancer, respectively. Thus, more investigations have been implemented to identify the potential SLCO1B3-related mechanisms of cancer drug resistance. In this review, we focus on the emerging roles of SLCO1B3 protein in the development of cancer chemotherapy resistance and briefly discuss the mechanisms of resistance. Elucidating the function of SLCO1B3 in chemoresistance may bring out novel therapeutic strategies for cancer treatment.

scholarly journals Insights into the structure and function of the human organic anion transporter 1 in lipid bilayer membranes

2022 ◽  
Author(s):  
Angelika Janaszkiewicz ◽  
Ágota Tóth ◽  
Quentin Faucher ◽  
Marving Martin ◽  
Benjamin Chantemargue ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Organic Anion ◽  
Major Facilitator Superfamily ◽  
Organic Anion Transporter ◽  
Lipid Bilayer Membranes ◽  
Bilayer Membranes ◽  
Anion Transporter ◽  
Functional Features ◽  
And Function ◽  
The Impact

The human SLC22A6/OAT1 plays an important role in the disposition of a broad range of endogenous substances and xenobiotics. This is particularly important from the pharmacological point of view since OAT1 is involved in drug elimination events. Furthermore, OAT1 is also involved in key physiological events such as the remote inter-organ communication. Despite its significance, the knowledge about OAT1 structure and the transport mechanism at the atomic level remains fragmented owing to the lack of resolved structures. By means of protein-threading modeling refined by μs-scaled Molecular Dynamics simulations, the present study provides the first robust model of hOAT1 in outward-facing conformation. Taking advantage of the AlphaFold 2 predicted structure of hOAT1 in inward-facing conformation, we here provide the essential structural and functional features comparing both states. The intracellular motifs conserved among Major Facilitator Superfamily members create a so-called "charge-relay system" that works as molecular switches modulating the conformation. The principal element of the event points at interactions charged residues that appear crucial for the transporter dynamics and function. Besides, hOAT1 model was embedded in different lipid bilayer membranes highlighting the crucial structural dependence on lipid-protein. MD simulations supported the pivotal role of phosphatidylethanolamine (PE) components on the protein conformation stability. The present model is made available to decipher the impact of any observed polymorphism and mutation on drug transport as well as to understand substrate binding modes.

A Decade’s Review of miRNA: a Center of Transcriptional Regulation of Drug-Metabolizing Enzymes and Transporters Under Hypoxia

2021 ◽  
Vol 22 ◽  
Author(s):  
Yabin Duan ◽  
Junbo Zhu ◽  
Jianxin Yang ◽  
Wenqi Gu ◽  
Xue Bai ◽  
...  
Keyword(s):  
Organic Anion ◽  
Hypoxia Inducible Factor ◽  
Organic Cation Transporter ◽  
Organic Anion Transporter ◽  
Peptide Transporter ◽  
Drug Metabolizing Enzymes ◽  
Cancer Resistance ◽  
Metabolizing Enzymes ◽  
Anion Transporter

Background: Hypoxia has a negative effect on the cardiovascular system, nervous system, and metabolism, which contributes to potential changes in drug absorption, distribution, metabolism, and excretion (ADME). However, hypoxia can also alter the expression of microRNA (miRNA), thereby regulating drug-metabolizing enzymes, transporters, and ADME genes, such as hypoxia-inducible factor, inflammatory cytokine, nuclear receptor, etc. Therefore, it is crucial to study the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Methods: A systematic review of published studies was carried out to investigate the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Data and information on expression changes in miRNA, drug-metabolizing enzymes, and transporters under hypoxia were analyzed and summarized Results: Hypoxia can up- or down-regulate the expression of miRNA. The effect of hypoxia on Cytochrome P450 (CYP450) is still a subject of debate. The widespread belief is that hypoxia decreased the activity and expression of CYP1A1, CYP1A2, CYP2E1, and CYP3A1 and increased those of CYP3A6 and CYP2D1 in rats. Hypoxia increased the expression of a multidrug resistance-associated protein, breast cancer resistance protein, peptide transporter, organic cation transporter, and organic anion transporter. miRNA negatively regulated the expression of drug-metabolizing enzymes and transporters. Conclusion: The findings of this review indicated that miRNA plays a key role in the expression changes of drug-metabolizing enzymes and transporters under hypoxia.

scholarly journals Mechanisms of glutathione-conjugate efflux from the brain into blood: Involvement of multiple transporters in the course

2018 ◽  
Vol 40 (1) ◽  
pp. 116-125 ◽  
Author(s):  
Toshimitsu Okamura ◽  
Maki Okada ◽  
Tatsuya Kikuchi ◽  
Hidekatsu Wakizaka ◽  
Ming-Rong Zhang
Keyword(s):  
Organic Anion ◽  
Organic Anion Transporter ◽  
Cancer Resistance ◽  
Efflux Rate ◽  
Glutathione Conjugate ◽  
Glutathione Conjugates ◽  
Anion Transporter ◽  
Significant Difference ◽  
The Brain

Accumulation of detrimental glutathione-conjugated metabolites in the brain potentially causes neurological disorders, and must therefore be exported from the brain. However, in vivo mechanisms of glutathione-conjugates efflux from the brain remain unknown. We investigated the involvement of transporters in glutathione-conjugates efflux using 6-bromo-7-[11C]methylpurine ([11C]1), which enters the brain and is converted into its glutathione conjugate, S-(7-[11C]methylpurin-6-yl)glutathione ([11C]2). In mice of control and knockout of P-glycoprotein/breast cancer resistance protein and multidrug resistance-associated protein 2 ([ Mrp2] −/−), [11C]2 formed in the brain was rapidly cleared, with no significant difference in efflux rate. In contrast, [11C]2 formed in the brain of Mrp1 −/− mice was slowly cleared, whereas [11C]2 microinjected into the brain of control and Mrp1 −/− mice was 75% cleared within 60 min, with no significant difference in efflux rate. These suggest that Mrp1 contributes to [11C]2 efflux across cell membranes, but not BBB. Efflux rate of [11C]2 formed in the brain was significantly lower in Mrp4 −/− and organic anion transporter 3 ( Oat3) −/− mice compared with control mice. In conclusion, Mrp1, Oat3, and Mrp4 mediate [11C]2 efflux from the brain. Mrp1 may contribute to [11C]2 efflux from brain parenchymal cells, while extracellular [11C]2 is likely cleared across the BBB, partly by Oat3 and Mrp4.

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