Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Pharmacokinetics

Murakami, Teruo; Mori, Nobuhiro

doi:10.3390/ph5080802

Cited by 31 publications

(15 citation statements)

References 150 publications

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“…MTX derivatives with chains longer than three glutamate residues are not substrates for the ABCC exporter proteins and have therefore enhanced cellular retention [51,53]. Polyglutamation is reversed by a deglutamation process, which is catalyzed by the γ-glutamyl hydrolase (GGH), producing a steady-state of intracellular MTX level [53,54]. MTX-polyglutamates are found in red blood cells, neutrophils, mononuclear cells, hepatocytes, and synoviocytes after oral administration [55].…”

Section: Pharmacokinetics Of Mtxmentioning

confidence: 99%

Methotrexate an Old Drug with New Tricks

Bedoui

Guillot

Sélambarom

et al. 2019

IJMS

312

192

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Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses—including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus—have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients’ immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.

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Section: Pharmacokinetics Of Mtxmentioning

confidence: 99%

Methotrexate an Old Drug with New Tricks

Bedoui

Guillot

Sélambarom

et al. 2019

IJMS

312

192

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“…In contrast to previous studies, we demonstrate that butyrate may exert its beneficial effects via influencing drug metabolism and excretion pathways. MTX is an anti-folate drug that penetrates the gastrointestinal tract through carrier-mediated transport system [30]. This drug is absorbed through proton-coupled folate transporters SLC46A1 and SLC19A1 and it effluxes from the cells by members of the ATP binding cassette transporters (ABC transporters), particularly ABCC1, ABCC2, ABCC3, ABCB10, ABCG5 and ABCG8 [31], [32].…”

Section: Discussionmentioning

confidence: 99%

Development of a self-limiting model of Methotrexate-induced mucositis reinforces butyrate as a potential therapy

Ferreira

Wehkamp

et al. 2020

Preprint

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Background: Gastrointestinal mucositis remains a significant complication of anticancer treatment, with limited anti-mucositis interventions. Currently, there are few validated in vitro systems suitable to study the mechanisms of mucosal injury. Therefore, we aimed to develop and characterize a chemotherapeutic-induced model of mucositis using 3D intestinal organoids. Methods: Organoids derived from mouse ileum were grown for 7 days and incubated with different concentrations of the chemotherapeutic agent methotrexate (MTX), ranging from 0-1000 ng/ml. Metabolic activity, citrulline levels and cytokine/chemokine production were measured to determine the optimal dosage and incubation time. To link the model to clinical practices, the protective effects of folinic acid on the toxicity of MTX were investigated by pre-treating organoids with (0.0005-50 µg/mL) folinic acid. Given the impact of microbial-derived short-chain fatty acids in epithelial health, we also evaluated the impact of short-chain fatty acid supplementation on MTX toxicity in the organoid model. Results: MTX treatment caused a dose-dependent reduction in cell metabolic activity and citrulline production. Folinic acid treatment reduced MTX toxicity when applied simultaneously or up to 24 hours after treatment. Supplementation of the growth medium with butyrate reduced MTX toxicity. Analysis of organoid gene expression suggests that butyrate may reduce intracellular MTX concentrations by increasing the expression of MTX transporters, including the ABCC1 transporter.Conclusion: MTX causes significant organoid damage, which can be reversed upon removal of MTX. The specific readouts and the protective effects of folinic acid suggest that the model is clinically relevant, and can be used in the future to study mucositis, diminishing the need for animal models. By using the model for intervention, it was found that prophylactic treatment with butyrate might be a valuable strategy for prophylactic mucositis prevention.

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“…Therefore, we hypothesized that these acidic metabolites of FS might modulate MRPs and BCRP. MRPs are distributed widely in the body, and transport a number of anticancer drugs such as methotrexate (MTX), vinblastine, 5-fluorouracil, doxorubicine and etoposide [32][33][34]. BCRP is located in brain, breast cells, liver, intestine, kidney, placenta, amd testis [19], and transports a number of anticancer drugs such as MTX, daunorubicin, doxorubicin, gefitinib, imatinib, ireinotecan, mitoxantrone and sunitinib [35].…”

Section: Effect Of Fs On Mtx Pharmacokinetics In Ratsmentioning

confidence: 99%

Folium Sennae Increased the Bioavailability of Methotrexate through Modulation on MRP 2 and BCRP

Peng

Huang

et al. 2021

Pharmaceuticals

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Folium Sennae (FS), a popular laxative (Senna), contains polyphenolic anthranoids, whose conjugation metabolites are probable modulators of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). We suspected that the combined use of FS might alter the pharmacokinetics of various medicines transported by MRPs or BCRP. This study investigated the effect of FS on the pharmacokinetics of methotrexate (MTX), an anticancer drug and a probe substrate of MRPs/BCRP. Rats were orally administered MTX alone and with two dosage regimens of FS in a parallel design. The results show that 5.0 g/kg of FS significantly increased the AUC0–2880, AUC720–2880 and MRT of MTX by 45%, 102% and 42%, and the seventh dose of 2.5 g/kg of FS significantly enhanced the AUC720–2880 and MRT by 78% and 42%, respectively. Mechanism studies indicated that the metabolites of FS (FSM) inhibited MRP 2 and BCRP. In conclusion, the combined use of FS increased the systemic exposure and MRT of MTX through inhibition on MRP 2 and BCRP.

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Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Pharmacokinetics

Cited by 31 publications

References 150 publications

Methotrexate an Old Drug with New Tricks

Methotrexate an Old Drug with New Tricks

Development of a self-limiting model of Methotrexate-induced mucositis reinforces butyrate as a potential therapy

Folium Sennae Increased the Bioavailability of Methotrexate through Modulation on MRP 2 and BCRP

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