Enantioselective Drug Recognition by Drug Transporters

Uwai, Yuichi

doi:10.3390/molecules23123062

Cited by 14 publications

(14 citation statements)

References 81 publications

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“…They are distributed in many tissues, but mainly act in the kidney (25). In the kidney, they are expressed in the basal lateral membrane of renal tubular epithelial cells (26,27), which promote the uptake of MTX from blood into renal tubular epithelial cells and mediate the urine excretion of MTX (28,29). Previous studies have shown that puerarin can inhibit the renal excretion of MTX by inhibiting the expression of OAT1/3, resulting in increased plasma MTX level (7).…”

Section: Discussionmentioning

confidence: 99%

Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp

Fu¹,

Wang²,

Guo³

et al. 2021

Ann Transl Med

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Background: Methotrexate (MTX) is an important anticancer agent and immunosuppressant with a narrow therapeutic window. Wuzhi capsule (WZC) is an extract of Schisandra which is widely used to treat liver diseases. Co-administration of MTX and WZC is common in the clinical setting, but research on the interaction between WZC and MTX is limited. This study aimed to investigate the effects of WZC on the pharmacokinetics of MTX in rats and to explore the role of membrane transport proteins OAT1/3 and P-gp in the interaction of these drugs.Methods: Plasma MTX concentration was detected by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS), and the messenger RNA (mRNA) and protein expression of OAT1/3 and P-gp was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analyses, respectively. Results:The study results revealed that co-administration of WZC decreased the CL z/F and V z/F of MTX, increased the C max and area under the curve [(AUC) 0-24 h ] of MTX, and inhibited OAT1/3 expression in the kidney and P-gp expression in the small intestine. Conclusions:The findings suggested that there is a drug interaction between WZC and MTX and that OAT1/3 in the kidney and P-gp in the small intestine may be the main targets mediating the drug interaction, and attention should be paid when they are used in combination.

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Section: Discussionmentioning

confidence: 99%

Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp

Fu¹,

Wang²,

Guo³

et al. 2021

Ann Transl Med

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“…Enantioselectivity is not expected during passive absorption of enantiomers; however, it may occur when a transport-mediated process is involved [ 14 ]. The peptide transporter PEPT1 is one of the most studied drug transporters in the intestine, as it helps to improve the absorption of previously poorly absorbed drugs, which makes it a target molecule [ 15 ]. Another well-studied transporter is the proton-coupled folate transporter (PCFT), which is located on the enterocyte membrane and is responsible for mediating folate absorption.…”

Section: Enantioselectivity In Drug Pharmacokineticsmentioning

confidence: 99%

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

et al. 2021

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Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed.

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“…Bioactive chiral compounds are structurally similar, but they can exhibit different biological activity and even potency [1,2]. A classic example is thalidomide, which has a therapeutic R -isomer and a teratogenic S -isomer.…”

Section: Introductionmentioning

confidence: 99%

Chiral Selectors in Capillary Electrophoresis: Trends during 2017–2018

Quirino

2019

Molecules

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Chiral separation is an important process in the chemical and pharmaceutical industries. From the analytical chemistry perspective, chiral separation is required for assessing the fit-for-purpose and the safety of chemical products. Capillary electrophoresis, in the electrokinetic chromatography mode is an established analytical technique for chiral separations. A water-soluble chiral selector is typically used. This review therefore examines the use of various chiral selectors in electrokinetic chromatography during 2017–2018. The chiral selectors were both low and high (macromolecules) molecular mass molecules as well as molecular aggregates (supramolecules). There were 58 papers found by search in Scopus, indicating continuous and active activity in this research area. The macromolecules were sugar-, amino acid-, and nucleic acid-based polymers. The supramolecules were bile salt micelles. The low molecular mass selectors were mainly ionic liquids and complexes with a central ion. A majority of the papers were on the use or preparation of sugar-based macromolecules, e.g., native or derivatised cyclodextrins. Studies to explain chiral recognition of macromolecular and supramolecular chiral selectors were mainly done by molecular modelling and nuclear magnetic resonance spectroscopy. Demonstrations were predominantly on drug analysis for the separation of racemates.

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Enantioselective Drug Recognition by Drug Transporters

Cited by 14 publications

References 81 publications

Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp

Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

Chiral Selectors in Capillary Electrophoresis: Trends during 2017–2018

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