scholarly journals Involvement of Organic Anion Transporters in the Pharmacokinetics and Drug Interaction of Rosmarinic Acid

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 83
Author(s):  
Yun Ju Kang ◽  
Chul Haeng Lee ◽  
Soo-Jin Park ◽  
Hye Suk Lee ◽  
Min-Koo Choi ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Rosmarinic Acid ◽  
Renal Excretion ◽  
Organic Anion ◽  
Plasma Concentrations ◽  
Pharmacokinetic Interaction ◽  
Organic Anion Transporter ◽  
Hek293 Cells ◽  
Anion Transporter

We investigated the involvement of drug transporters in the pharmacokinetics of rosmarinic acid in rats as well as the transporter-mediated drug interaction potential of rosmarinic acid in HEK293 cells overexpressing clinically important solute carrier transporters and also in rats. Intravenously injected rosmarinic acid showed bi-exponential decay and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion. Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a Km of 26.5 μM and a Vmax of 69.0 pmol/min in HEK293 cells overexpressing OAT1, and the plasma concentrations of rosmarinic acid were increased by the co-injection of probenecid because of decreased renal excretion due to OAT1 inhibition. Rosmarinic acid inhibited the transport activities of OAT1, OAT3, organic anion transporting polypeptide (OATP)1B1, and OATP1B3 with IC50 values of 60.6 μM, 1.52 μM, 74.8 μM, and 91.3 μM, respectively, and the inhibitory effect of rosmarinic acid on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. In conclusion, OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions with rosmarinic acid, although their clinical relevance awaits further evaluation.

scholarly journals Interactions of 172 plant extracts with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8): a study on herb-drug interactions

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3333 ◽  
Author(s):  
Hang Lu ◽  
Zhiqiang Lu ◽  
Xue Li ◽  
Gentao Li ◽  
Yilin Qiao ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Plant Extracts ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Hek293 Cells ◽  
Pharmacokinetic Parameters ◽  
Renal Elimination ◽  
Juncus Effusus ◽  
Anion Transporter

BackgroundHerb-drug interactions (HDIs) resulting from concomitant use of herbal products with clinical drugs may cause adverse reactions. Organic anion transporter 1 (OAT1) and 3 (OAT3) are highly expressed in the kidney and play a key role in the renal elimination of substrate drugs. So far, little is known about the herbal extracts that could modulate OAT1 and OAT3 activities.MethodsHEK293 cells stably expressing human OAT1 (HEK-OAT1) and OAT3 (HEK-OAT3) were established and characterized. One hundred seventy-two extracts from 37 medicinal and economic plants were prepared. An initial concentration of 5 µg/ml for each extract was used to evaluate their effects on 6-carboxylfluorescein (6-CF) uptake in HEK-OAT1 and HEK-OAT3 cells. Concentration-dependent inhibition studies were conducted for those extracts with more than 50% inhibition to OAT1 and OAT3. The extract ofJuncus effusus, a well-known traditional Chinese medicine, was assessed for its effect on thein vivopharmacokinetic parameters of furosemide, a diuretic drug which is a known substrate of both OAT1 and OAT3.ResultsMore than 30% of the plant extracts at the concentration of 5 µg/ml showed strong inhibitory effect on the 6-CF uptake mediated by OAT1 (61 extracts) and OAT3 (55 extracts). Among them, three extracts for OAT1 and fourteen extracts for OAT3 were identified as strong inhibitors with IC50values being <5 µg/ml.Juncus effususshowed a strong inhibition to OAT3in vitro, and markedly altered thein vivopharmacokinetic parameters of furosemide in rats.ConclusionThe present study identified the potential interactions of medicinal and economic plants with human OAT1 and OAT3, which is helpful to predict and to avoid potential OAT1- and OAT3-mediated HDIs.

A novel hydrophilic interaction chromatography assay characterization of 4-pyridoxic acid, an emergent renal organic anion transporter 1/3 transporter biomarker

Bioanalysis ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 1391-1400
Author(s):  
Justin Towner ◽  
Brian Rago ◽  
David Rodrigues ◽  
Manoli Vourvahis ◽  
Chris Holliman
Keyword(s):  
Drug Interaction ◽  
Clinical Studies ◽  
Organic Anion ◽  
Plasma Concentrations ◽  
Hydrophilic Interaction Chromatography ◽  
Organic Anion Transporter ◽  
Hydrophilic Interaction ◽  
Anion Transporter ◽  
Clinical Drug

Aim: 4-pyridoxic acid (PDA) has been proposed as an endogenous biomarker for renal organic anion transporter 1/3 (OAT1/3) inhibition. Clinical data are needed to support the proposal. Materials & methods: A hydrophilic interaction chromatography (HILIC)–LC/MS/MS assay was developed and characterized to support clinical drug–drug interaction (DDI) studies. Results: A HILIC–LC/MS/MS assay was successfully developed. PDA was measured in two clinical DDI studies; one where no significant OAT1/3 inhibition was observed and a second where a known inhibitor of the transporter was dosed. In both clinical studies, PDA plasma concentrations correlate to OAT1/3 function. Conclusion: The analysis of study samples from two clinical DDI studies using a HILIC–LC/MS/MS assay contributes further evidence that PDA is an endogenous biomarker for OAT1/3 inhibition.

scholarly journals Drug interaction between celecoxib and methotrexate in organic anion transporter 3–transfected renal cells and in rats in vivo

2010 ◽  
Vol 640 (1-3) ◽  
pp. 168-171 ◽  
Author(s):  
Akimitsu Maeda ◽  
Shuichi Tsuruoka ◽  
Kentarou Ushijima ◽  
Yoshikatsu Kanai ◽  
Hitoshi Endou ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Renal Cells ◽  
Anion Transporter ◽  
Organic Anion Transporter 3

scholarly journals Application of a PBPK Model of Rivaroxaban to Prospective Simulations of Drug-Drug-Disease Interactions with Protein Kinase Inhibitors in CA-VTE

2021 ◽  
Author(s):  
Eleanor Jing Yi Cheong ◽  
Daniel Zhi Wei Ng ◽  
Sheng Yuan Chin ◽  
Ziteng Wang ◽  
Eric Chun Yong Chan
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Pbpk Model ◽  
Organic Anion ◽  
Protein Kinase Inhibitors ◽  
Organic Anion Transporter ◽  
Pbpk Modelling ◽  
Anion Transporter

Background and Purpose Rivaroxaban is emerging as a viable anticoagulant for the pharmacological management of cancer associated venous thromboembolism (CA-VTE). Being eliminated via CYP3A4/2J2-mediated metabolism and organic anion transporter 3 (OAT3)/P-glycoprotein-mediated renal secretion, rivaroxaban is susceptible to drug-drug interactions (DDIs) with protein kinase inhibitors (PKIs), erlotinib and nilotinib. Physiologically based pharmacokinetic (PBPK) modelling was applied to interrogate the DDIs for dose adjustment of rivaroxaban in CA-VTE. Experimental Approach The inhibitory potencies of erlotinib and nilotinib on CYP3A4/2J2-mediated metabolism of rivaroxaban were characterized. Using prototypical OAT3 inhibitor ketoconazole, in vitro OAT3 inhibition assays were optimized to ascertain the in vivo relevance of derived inhibitory constants (K). DDIs between rivaroxaban and erlotinib or nilotinib were investigated using iteratively verified PBPK model. Key Results Mechanism-based inactivation (MBI) of CYP3A4-mediated rivaroxaban metabolism by both PKIs and MBI of CYP2J2 by erlotinib were established. The importance of substrate specificity and nonspecific binding to derive OAT3-inhibitory K values of ketoconazole and nilotinib for the accurate prediction of DDIs was illustrated. When simulated rivaroxaban exposure variations with concomitant erlotinib and nilotinib therapy were evaluated using published dose-exposure equivalence metrics and bleeding risk analyses, dose reductions from 20 mg to 15 mg and 10 mg in normal and mild renal dysfunction, respectively, were warranted. Conclusion and Implications We established the PBPK-DDI platform to prospectively interrogate and manage clinically relevant interactions between rivaroxaban and PKIs in patients with underlying renal impairment. Rational dose adjustments were proposed, attesting to the capacity of PBPK modelling in facilitating precision medicine.

Inhibition of initial transport rate of basolateral organic anion carrier in renal PT by BK and phenylephrine

1999 ◽  
Vol 277 (2) ◽  
pp. F251-F256 ◽  
Author(s):  
Michael Gekle ◽  
Sigrid Mildenberger ◽  
Christoph Sauvant ◽  
Dallas Bednarczyk ◽  
Stephen H. Wright ◽  
...  
Keyword(s):  
Direct Action ◽  
Organic Anion ◽  
Specific Inhibitor ◽  
Peptide Hormone ◽  
Organic Anion Transporter ◽  
Epifluorescence Microscopy ◽  
Anion Transporter ◽  
Initial Uptake Rate ◽  
Continuous Presence

The effect of ligands for phospholipase C-coupled receptors and of protein kinase C (PKC) stimulation with phorbol ester [phorbol 12-myristate 13-acetate (PMA)] or 1,2-dioctanoyl- sn-glycerol on the activity of the basolateral organic anion transporter (OAT) in S2 segments of single, nonperfused rabbit proximal tubules (PT) was measured with the use of fluorescein and epifluorescence microscopy. The initial uptake rate (25 s, OAT activity) was measured in real time by using conditions similar to those found in vivo. Stimulation of PKC with PMA or 1,2-dioctanoyl- sn-glycerol led to an inhibition of OAT activity, which could be prevented by 10−7 mol/l of the PKC-specific inhibitor bisindolylmaleimide. The α1-receptor agonist phenylephrine as well as the peptide hormone bradykinin induced a reversible decrease of OAT activity, which was prevented by bisindolylmaleimide. The observed effect was not due to a decrease in the concentration of the counterion α-ketoglutarate or to impaired α-ketoglutarate recycling, because it was unchanged in the continuous presence of α-ketoglutarate or methyl succinate. We conclude that physiological stimuli can inhibit the activity of OAT in rabbit PT via PKC. The effect is not mediated by alterations in counterion availability but by a direct action on the OAT.

Renal Organic Anion Transporter-Mediated Drug-Drug Interaction between Gemcabene and Quinapril

2009 ◽  
Vol 330 (1) ◽  
pp. 191-197 ◽  
Author(s):  
Haodan Yuan ◽  
Bo Feng ◽  
Ying Yu ◽  
Jonathan Chupka ◽  
Jenny Y. Zheng ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Anion Transporter ◽  
Drug Drug Interaction

scholarly journals In vivo Cisplatin Resistance Depending upon Canalicular Multispecific Organic Anion Transporter (cMOAT)

1999 ◽  
Vol 90 (10) ◽  
pp. 1171-1178 ◽  
Author(s):  
Tomoyoshi Minamino ◽  
Mitsuo Tamai ◽  
Yoshie Itoh ◽  
Yasuaki Tatsumi ◽  
Masaaki Nomura ◽  
...  
Keyword(s):  
Cisplatin Resistance ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Anion Transporter

scholarly journals Cytotoxicity of Antiviral Nucleotides Adefovir and Cidofovir Is Induced by the Expression of Human Renal Organic Anion Transporter 1

2000 ◽  
Vol 11 (3) ◽  
pp. 383-393 ◽  
Author(s):  
EDMUND S. HO ◽  
DEBORAH C. LIN ◽  
DIRK B. MENDEL ◽  
TOMAS CIHLAR
Keyword(s):  
Organic Anion ◽  
Critical Role ◽  
Antiviral Agents ◽  
Chinese Hamster ◽  
Organic Anion Transporter ◽  
Nucleotide Analogs ◽  
Anion Transporter ◽  
Organ Specific

Abstract. The transport of organic anions in proximal convoluted tubules plays an essential role in the active secretion of a variety of small molecules by the kidney. In addition to other anionic substrates, the human renal organic anion transporter 1 (hOAT1) is capable of transporting the nucleotide analogs adefovir and cidofovir. To investigate the involvement of hOAT1 in the mechanism of nephrotoxicity associated with these two clinically important antiviral agents, Chinese hamster ovary (CHO) cells were stably transfected with hOAT1 cDNA. The resulting CHOhOAT cells showed probenecid-sensitive and pH-dependent uptake of p-aminohippurate (Km = 15.4 μM, Vmax = 20.6 pmol/106 cells · min), a prototypical organic anion substrate. In addition, the stably expressed hOAT1 mediated efficient transport of adefovir (Km = 23.8 μM, Vmax = 46.0 pmol/106 cells · min) and cidofovir (Km = 58.0 μM, Vmax = 103 pmol/106 cells · min) such that the levels of intracellular metabolites of both nucleotides were >100-fold higher in CHOhOAT cells than in parental CHO. Consequently, adefovir and cidofovir were approximately 500-fold and 400-fold more cytotoxic, respectively, in CHOhOAT cells compared to CHO. The cytotoxicity of both drugs in CHOhOAT cells was markedly reduced in the presence of hOAT1 inhibitors. The cyclic prodrug of cidofovir, which exhibits reduced in vivo nephrotoxicity, was a poor substrate for hOAT1 and showed only marginally increased cytotoxicity in CHOhOAT cells. In conclusion, these studies demonstrate that hOAT1 plays a critical role in the organ-specific toxicity of adefovir and cidofovir, and indicates that CHOhOAT cells may represent a useful in vitro model to investigate the potential nephrotoxicity of clinically relevant organic anion agents.

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