The role of organic anion transporting polypeptides in drug absorption, distribution, excretion and drug-drug interactions

Kovacsics, Daniella; Patik, Izabel; Özvegy‐Laczka, Csilla

doi:10.1080/17425255.2017.1253679

Cited by 66 publications

(53 citation statements)

References 158 publications

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“…At least four members of the family (i.e., OATP1A2, OATP1B1, OATP1B3, OATP2B1) transport various clinically applied drugs, in addition to endobiotics. Therefore, these proteins are also key determinants of drug absorption, distribution, and excretion (Kovacsics et al, 2016). …”

Section: Intracrine Actions Of Steroid Hormonesmentioning

confidence: 99%

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

2017

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Endometrial and ovarian cancers predominately affect women after menopause, and are more frequently observed in developed countries. These are considered to be hormone-dependent cancers, as steroid hormones, and estrogens in particular, have roles in their onset and progression. After the production of estrogens in the ovary has ceased, estrogen synthesis occurs in peripheral tissues. This depends on the cellular uptake of estrone-sulfate and dehydroepiandrosterone-sulfate, as the most important steroid precursors in the plasma of postmenopausal women. The uptake through transporter proteins, such as those of the organic anion-transporting polypeptide (OATP) and organic anion-transporter (OAT) families, is followed by the synthesis and action of estradiol E2. Here, we provide an overview of the current understanding of this intracrine action of steroid hormones, which depends on the availability of the steroid precursors and transmembrane transporters for precursor uptake, along with the enzymes for the synthesis of E2. The data is also provided relating to the selected transmembrane transporters from the OATP, OAT, SLC51, and ABC-transporter families, and the enzymes involved in the E2-generating pathways in cancers of the endometrium and ovary. Finally, we discuss these transporters and enzymes as potential drug targets.Keywords: sulfatase, aromatase, 17beta-hydroxysteroid dehydrogenase, transporters, OATP, ABC-transporter HORMONE-DEPENDENT CANCERSSteroid hormones have important roles in human physiology, and the disruption of androgen, estrogen, and progesterone actions are implicated in the development of hormone-dependent cancers and benign hormone-dependent diseases. Hormone-dependent cancers include prostate, breast, endometrial, and ovarian cancers, which comprise more than 20% of all cancers in humans, and more than 35% of cancers in women (Ferlay et al., 2013). Indeed, in women, breast cancer is the most frequent cancer in the developed world. In 2012, 1,671,149 new cases of breast cancer were estimated worldwide, with 521,907 associated deaths. In the developed world, endometrial cancer is the most common among gynecological cancers. Worldwide, there were 319,605 new cases and 76,160 deaths from endometrial cancer in 2012 alone (Ferlay et al., 2013). The most deadly of the hormone-dependent cancers is ovarian cancer. Worldwide, there were 238,719 new cases and 151,905 deaths from ovarian cancer in 2012 (Ferlay et al., 2013).

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Section: Intracrine Actions Of Steroid Hormonesmentioning

confidence: 99%

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

2017

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“…The major physiological substrates of OATPs are steroid and thyroid hormones, prostaglandins, bile acids, and bilirubin . However, several members of the OATP family, OATPs, 1A2, 1B1/1B3, and 2B1, are multispecific transporters that recognize a large variety of chemically diverse molecules, including not only endogenous substrates but also clinically applied drugs, for example, antivirals, chemotherapeutics, and statins . These polyspecific OATPs therefore influence drug absorption, distribution, and toxicity, and have been in the focus of extensive research .…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, there is increasing evidence that OATP1A2 plays an important role in drug penetration into the CNS by regulating drug entry into the BBB endothelial cells and also in drug absorption/re‐absorption in the bile duct and in the kidney . Endogenous substrates of OATP1A2 include bile acids, bilirubin, steroid and thyroid hormones, prostaglandin E2, and all‐trans‐retinol . In addition, OATP1A2 mediates the cellular intake of numerous chemically unrelated compounds from antihistamines through statins to chemotherapeutic agents .…”

Section: Introductionmentioning

confidence: 99%

A novel fluorescence‐based functional assay for human OATP1A2 and OATP1C1 identifies interaction between third‐generation P‐gp inhibitors and OATP1A2

et al. 2019

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Organic anion‐transporting polypeptide 1A2 (OATP1A2), expressed in the human blood–brain barrier, promotes drug uptake from the blood and hence can be exploited for central nervous system‐targeted drug delivery. The thyroid transporter OATP1C1, expressed in the choroid plexus and in astrocytes, is also a potential pharmacological target. Based on their established pharmacological relevance, screening the drug interaction profile of OATP1A2 and OATP1C1 is highly desirable. However, drug interaction screens require suitable model systems and functional assays. In the current study, uptake of a set of cell‐impermeable fluorescent dyes was screened in HEK‐293 and A431 cell lines overexpressing OATP1A2 and OATP1C1. Based on the uptake of fluorescent dye substrates, a functional assay was developed, which was used to characterize OATP inhibitors/substrates. We identify Live/Dead Green (LDG), Live‐or‐Dye 488, and sulforhodamines 101, G, and B as novel fluorescent substrates of OATP1A2 and OATP1C1. We show that LDG uptake is proportional to OATP1A2/1C1 expression, allowing the isolation of cells expressing high transporter levels. Additionally, dye uptake can be used to characterize the drug interaction pattern of OATP1A2 and OATP1C1. We demonstrate that third‐generation P‐glycoprotein inhibitors elacridar, tariquidar, and zosuquidar inhibit OATP1A2 function. Increased toxicity of elacridar in OATP1A2‐expressing cells suggests that OATP1A2 may modulate the distribution of this compound. The fluorescence‐based assays developed in the current study are a good alternative of radioligand‐based tests and pave the way toward high‐throughput screens for OATP1A2/1C1 drug interaction studies.

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“…Human hepatocytes express the transporters OATP1B1 (encoded by SLCO1B1), OATP1B3 246 (encoded by SLCO1B3) and OATP2B1 (encoded by SLCO2B1 37 . Potentially hepatotoxic substrates 247 include statins (used to treat hypercholesterolemia), and plasma statin levelsa risk factor for 248 statin-induced myopathyincrease in the presence of OATP1B1 inhibitors such as cyclosporin A 249 (an immunosuppressant) or gemfibrozil (a lipid-lowering agent) 38,39 . Several tyrosine kinase 250 inhibitors (TKIs, which are small molecules used to treat various forms of cancer) are substrates 251 and/or inhibitors of OATPs.…”

mentioning

confidence: 99%

Drug-induced liver injury

Andrade

Chalasani

Bjõrnsson

et al. 2019

Nat Rev Dis Primers

531

338

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Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when the subject is exposed to toxic doses of some compounds (acetaminophen overdose) or in an unpredictable way with many drugs in common use. Drugs can be harmful to the liver in a susceptible subject on the background of genetic and environmental factors. This accounts for modifications in the hepatic metabolism and excretion of the agent leading to cellular stress, direct cell death, activation of an adaptive immune response and a failure to adapt with progression to overt liver injury. Idiosyncratic DILI is a relative rare liver disorder but can be severe and even fatal, presenting with a variety of phenotypes, which mimic almost every other liver disease. Diagnosis of DILI relies on the exclusion of other etiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need a refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has yet been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune checkpoint inhibitors.

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The role of organic anion transporting polypeptides in drug absorption, distribution, excretion and drug-drug interactions

Cited by 66 publications

References 158 publications

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

A novel fluorescence‐based functional assay for human OATP1A2 and OATP1C1 identifies interaction between third‐generation P‐gp inhibitors and OATP1A2

Drug-induced liver injury

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