scholarly journals Interaction of Hydroxychloroquine with Pharmacokinetically Important Drug Transporters

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 919
Author(s):  
Johanna Weiss ◽  
Gzona Bajraktari-Sylejmani ◽  
Walter E. Haefeli
Keyword(s):  
Cell Lines ◽  
Drug Transporters ◽  
Organic Anion ◽  
Parental Cell ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Organic Anion Transporting Polypeptide ◽  
Aryl Hydrocarbon ◽  
Mrna Induction ◽  
Uptake Transporters

(1) Background: Hydroxychloroquine is used to treat malaria and autoimmune diseases, and its potential use against COVID-19 is currently under investigation. Thus far, information on interactions of hydroxychloroquine with drug transporters mediating drug-drug interactions is limited. We assessed the inhibition of important efflux (P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)) and uptake transporters (organic anion transporting polypeptide (OATP)-1B1, OATP1B3, OATP2B1) by hydroxychloroquine, tested its P-gp and BCRP substrate characteristics, and evaluated the induction of pharmacokinetically relevant genes regulated by the nuclear pregnane X (PXR) (CYP3A4, ABCB1) and aryl hydrocarbon receptor (AhR) (CYP1A1, CYP1A2). (2) Methods: Transporter inhibition was evaluated in transporter over-expressing cell lines using fluorescent probe substrates. P-gp and BCRP substrate characteristics were assessed by comparing growth inhibition of over-expressing and parental cell lines. Possible mRNA induction was analysed in LS180 cells by quantitative real-time PCR. (3) Results: Hydroxychloroquine did not inhibit BCRP or the OATPs tested but inhibited P-gp at concentrations exceeding 10 µM. P-gp overexpressing cells were 5.2-fold more resistant to hydroxychloroquine than control cells stressing its substrate characteristics. Hydroxychloroquine did not induce genes regulated by PXR or AhR. (4) Conclusions: This is the first evidence that hydroxychloroquine’s interaction potential with drug transporters is low, albeit bioavailability of simultaneously orally administered P-gp substrates might be increased by hydroxychloroquine.

DNA Methylation Profiles of Organic Anion Transporting Polypeptide 1B3 in Cancer Cell Lines

2010 ◽  
Vol 27 (3) ◽  
pp. 510-516 ◽  
Author(s):  
Sayaka Ichihara ◽  
Ryota Kikuchi ◽  
Hiroyuki Kusuhara ◽  
Satoki Imai ◽  
Kazuya Maeda ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Lines ◽  
Cancer Cell ◽  
Organic Anion ◽  
Cancer Cell Lines ◽  
Organic Anion Transporting Polypeptide

scholarly journals Imaging of hepatic drug transporters with [131I]6-β-iodomethyl-19-norcholesterol

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Masato Kobayashi ◽  
Kodai Nishi ◽  
Asuka Mizutani ◽  
Tsuzumi Hokama ◽  
Miki Matsue ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Human Liver ◽  
Drug Transporters ◽  
Organic Anion ◽  
Hek293 Cells ◽  
Emission Computed Tomography ◽  
Cancer Resistance ◽  
Mouse Blood ◽  
Hepatic Drug ◽  
Resistance Protein

Abstract We examined whether [131I]6-β-iodomethyl-19-norcholesterol (NP-59), a cholesterol analog, can be used to measure function of hepatic drug transporters. Hepatic uptake of NP-59 with and without rifampicin was evaluated using HEK293 cells expressing solute carrier transporters. The stability of NP-59 was evaluated using mouse blood, bile, and liver, and human liver S9. Adenosine triphosphate-binding cassette (ABC) transporters for bile excretion were examined using hepatic ABC transporter vesicles expressing multidrug resistance protein 1, multidrug resistance-associated protein (MRP)1-4, breast cancer resistance protein (BCRP), or bile salt export pump with and without MK-571 and Ko143. Single photon emission computed tomography (SPECT) was performed in normal mice injected with NP-59 in the presence or absence of Ko143. Uptake of NP-59 into HEK293 cells expressing organic anion transporting polypeptide (OATP)1B1 and OATP1B3 was significantly higher than that into mock cells and was inhibited by rifampicin. NP-59 was minimally metabolized in mouse blood, bile, and liver, and human liver S9 after 120 min of incubation. In vesicles, NP-59 was transported by MRP1 and BCRP. Excretion of NP-59 into bile via BCRP was observed in normal mice with and without Ko143 in the biological distribution and SPECT imaging. NP-59 can be used to visualize and measure the hepatic function of OATP1B1, OATP1B3, and BCRP.

scholarly journals Raltegravir Has a Low Propensity To Cause Clinical Drug Interactions through Inhibition of Major Drug Transporters: anIn VitroEvaluation

2013 ◽  
Vol 58 (3) ◽  
pp. 1294-1301 ◽  
Author(s):  
Matthew L. Rizk ◽  
Robert Houle ◽  
Grace Hoyee Chan ◽  
Mike Hafey ◽  
Elizabeth G. Rhee ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Cation ◽  
Drug Transporters ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Hepatic Uptake ◽  
Efflux Transporters ◽  
Renal Uptake ◽  
No Inhibition ◽  
Uptake Transporters

ABSTRACTRaltegravir (RAL) is a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. The potential of RAL to cause transporter-related drug-drug interactions (DDIs) as an inhibitor has not been well described to date. In this study, a series ofin vitroexperiments were conducted to assess the inhibitory effects of RAL on major human drug transporters known to be involved in clinically relevant drug interactions, including hepatic and renal uptake transporters and efflux transporters. For hepatic uptake transporters, RAL showed no inhibition of organic anion-transporting polypeptide 1B1 (OATP1B1), weak inhibition of OATP1B3 (40% inhibition at 100 μM), and no inhibition of organic cation transporter 1 (OCT1). Studies of renal uptake transporters showed that RAL inhibited organic anion transporters 1 and 3 (OAT1 and OAT3) with 50% inhibitory concentrations (IC50s) (108 μM and 18.8 μM, respectively) well above the maximum concentration of drug in plasma (Cmax) at the clinical 400-mg dose and did not inhibit organic cation transporter 2 (OCT2). As for efflux transporters, RAL did not inhibit breast cancer resistance protein (BCRP) and showed weak inhibition of multidrug and toxin extrusion protein 1 (MATE1) (52% inhibition at 100 μM) and MATE2-K (29% inhibition at 100 μM). These studies indicate that at clinically relevant exposures, RAL does not inhibit or only weakly inhibits hepatic uptake transporters OATP1B1, OATP1B3, and OCT1, renal uptake transporters OCT2, OAT1, and OAT3, as well as efflux transporters BCRP, MATE1, and MATE2-K. The propensity for RAL to cause DDIs via inhibition of these transporters is therefore considered low.

scholarly journals Enantioselective Drug Recognition by Drug Transporters

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3062 ◽  
Author(s):  
Yuichi Uwai
Keyword(s):  
Drug Transporters ◽  
Organic Anion ◽  
Cancer Resistance ◽  
Multidrug Resistance Proteins ◽  
Inhibitory Effects ◽  
Organic Anion Transporting Polypeptides ◽  
Resistance Proteins ◽  
Anion Transporters ◽  
Resistance Protein ◽  
The Relationship

Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect. Enantioselectivity in the transport of drugs by drug transporters and the inhibitory effects of drugs on drug transporters has been summarized in this review.

scholarly journals The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates

2022 ◽  
Vol 12 ◽  
Author(s):  
Erkka Järvinen ◽  
Feng Deng ◽  
Wilma Kiander ◽  
Alli Sinokki ◽  
Heidi Kidron ◽  
...  
Keyword(s):  
Phase Ii ◽  
Organic Anion ◽  
The Body ◽  
Cell Membrane Permeability ◽  
Intestinal Lumen ◽  
Efflux Transporters ◽  
Cancer Resistance ◽  
Multidrug Resistance Proteins ◽  
Uptake Transporters

Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.

scholarly journals YQ36: A Novel Bisindolylmaleimide Analogue Induces KB/VCR Cell Death

2009 ◽  
Vol 2009 ◽  
pp. 1-11
Author(s):  
Ji Cao ◽  
Lei Zhang ◽  
Qing Ye ◽  
Xinglu Zhou ◽  
Jianshu Lou ◽  
...  
Keyword(s):  
Dna Damage ◽  
Multidrug Resistance ◽  
Cell Lines ◽  
Parental Cell ◽  
Mitochondrial Pathway ◽  
Chemotherapeutic Agents ◽  
Multidrug Resistance Proteins ◽  
Glycoprotein P ◽  
Resistance Proteins ◽  
P Glycoprotein

Overexpression of multidrug resistance proteins P-glycoprotein (P-gp, MDR1) causes resistance of the tumor cells against a variety of chemotherapeutic agents. 3-(1-methyl-1H-indol-3-yl)-1-phenyl-4-(1-(3-(piperidin-1-yl)propyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1H-pyrrole-2,5-dione (YQ36) is a novel analogue of bisindolylmaleimide, which has been reported to overcome multidrug resistance. Here, we dedicated to investigate the anticancer activity of YQ36 on KB/VCR cells. The results revealed that YQ36 exhibited great antiproliferative activity on three parental cell lines and MDR1 overexpressed cell lines. Moreover, the hypersensitivity of YQ36 was confirmed on the base of great apoptosis induction and unaltered intracellular drug accumulation in KB/VCR cells. Further results suggested that YQ36 could not be considered as a substrate of P-gp, which contributed to its successfully escaping from the efflux mediated by P-gp. Interestingly, we observed that YQ36 could accumulate in nucleus and induce DNA damage. YQ36 could also induce the activation of caspase-3, imposing effects on the mitochondrial function. Collectively, our data demonstrated that YQ36 exhibited potent activities against MDR cells, inducing DNA damage and triggering subsequent apoptosis via mitochondrial pathway.

Constituents of Passiflora incarnata, but Not of Valeriana officinalis, Interact with the Organic Anion Transporting Polypeptides (OATP)2B1 and OATP1A2

Planta Medica ◽  
2021 ◽  
Author(s):  
Anima M. Schäfer ◽  
Pierrine M. Gilgen ◽  
Clara Spirgi ◽  
Olivier Potterat ◽  
Henriette E. Meyer zu Schwabedissen
Keyword(s):  
Organic Anion ◽  
Dehydroepiandrosterone Sulfate ◽  
Valeriana Officinalis ◽  
Organic Anion Transporting Polypeptides ◽  
Organic Anion Transporting Polypeptide ◽  
Sulfated Steroids ◽  
Valerenic Acid ◽  
Passiflora Incarnata ◽  
Uptake Transporters ◽  
Darby Canine Kidney

AbstractHerbal medication used in the treatment of sleep disorders and anxiety often contain extracts of Valeriana officinalis or Passiflora incarnata. Valerenic acid in V. officinalis and apigenin, orientin, and vitexin in P. incarnata are thought to contribute to their therapeutic effect. It was the aim of this study to test whether these constituents of herbal extracts are interacting with the uptake of estrone 3-sulfate, pregnenolone sulfate, and dehydroepiandrosterone sulfate mediated by the uptake transporters organic anion transporting polypeptide 2B1 (OATP2B1) or organic anion transporting polypeptide 1A2 (OATP1A2). Madin-Darby canine kidney cells overexpressing OATP2B1 or OATP1A2 were used to determine the influence of the constituents on the cellular accumulation of the sulfated steroids. Subsequently, competitive counterflow experiments were applied to test whether identified inhibitors are also substrates of the transporters. Valerenic acid only interacted with OATP2B1, whereas apigenin, orientin, and vitexin interacted with OATP2B1 and OATP1A2. Competitive counterflow revealed that orientin is a substrate of both transporters, while apigenin was transported by OATP1A2 and vitexin by OATP2B1. In a next step, commercially available P. incarnata preparations were assessed for their influence on the transporters, revealing inhibition of transporter-mediated estrone 3-sulfate uptake. HPLC-UV-MS analysis confirmed the presence of orientin and vitexin in these preparations, thereby suggesting that these constituents are involved in the interaction. Our data indicate that constituents of P. incarnata may alter the function of OATP2B1 and OATP1A2, which could affect the uptake of other compounds relying on uptake mediated by the transporters.

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