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. 2024 Mar 15;32(1):103–111. doi: 10.38212/2224-6614.3495

An acute herb–drug interaction of Magnoliae Officinalis Cortex with methotrexate via inhibiting multidrug resistance-associated protein 2

Chung-Ping Yu a,b, Pei-Ying Li a, Szu-Yu Chen a, Shiuan-Pey Lin a, Ying-Chen Chen c, Lu-Ching Ho a,b, Yow-Wen Hsieh a,b, Yu-Chi Hou a,b,*
PMCID: PMC10962649  PMID: 38526588

Abstract

Magnoliae Officinalis Cortex (MOC), an herbal drug, contains polyphenolic lignans mainly magnolol (MN) and honokiol (HK). Methotrexate (MTX), a critical drug for cancers and autoimmune deseases, is a substrate of multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). This study investigated the effect of coadministration of MOC on the pharmacokinetics of MTX and relevant mechanisms. Sprague–Dawley rats were orally administered MTX alone and with single dose (2.0 and 4.0 g/kg) and repeated seven doses of MOC (2.0 g/kg thrice daily for 2 days, the 7th dose given at 0.5 h before MTX). The serum concentrations of MTX were determined by a fluorescence polarization immunoassay. The results showed that a single dose of MOC at 2.0 g/kg significantly increased the AUC0-t and MRT of MTX by 352% and 308%, and a single dose at 4.0 g/kg significantly enhanced the AUC0-t and MRT by 362% and 291%, respectively. Likewise, repeated seven doses of MOC at 2.0 g/kg significantly increased the AUC0-t and MRT of MTX by 461% and 334%, respectively. Mechanism studies indicated that the function of MRP2 was significantly inhibited by MN, HK and the serum metabolites of MOC (MOCM), whereas BCRP was not inhibited by MOCM. In conclusion, coadministration of MOC markedly enhanced the systemic exposure and mean residence time of MTX through inhibiting the MRP2-mediated excretion of MTX.

Keywords: Herb-drug interaction, Magnoliae Officinalis Cortex, Methotrexate, MRP2, Pharmacokinetics

1. Introduction

Magnoliae Officinalis Cortex (MOC), the dried bark of Magnolia officinalis Rehder & E.H. Wilson), is a widely prescribed herbal medicine in Asia countries for thousand years. According to the 4th Taiwan Herbal Pharmacopeia, the indications of MOC are for drying dampness and resolving phlegm, directing qi downward and eliminating fullness. The usual daily dose of MOC is 3.0–11.5 g. Nowadays, MOC is often used for the treatments of a variety of disorders, such as digestive disturbance, mental diseases and allergic diseases [1–3]. The major constituents of MOC are magnolol (MN) and honokiol (HK), which are polyphenolic lignans exhibiting various beneficial activities, such as anti-inflammation [4], anti-spasmodic [5], anti-anxiety [6,7] and anti-cancer effects [8]. Therefore, MOC and its components are contained in many nutraceuticals available in recent markets [9,10].

Based on previous pharmacokinetic studies, the conjugated metabolites of MN and HK are abundant in the bloodstream after oral administrations of MN, HK or MOC [10–12]. In recent decades, the conjugated metabolites existing as anions in the blood were known as substrates of multidrug resistance-associated proteins (MRPs) or breast cancer resistance protein (BCRP) [13–15]. Besides, our recent study verified that MN and HK were substrates and inhibitors of BCRP [16]. Because MRP2 and BCRP are efflux drug transporters expressed at the apical membranes of multiple tissues, including intestine, liver and kidney tubules [17], the inhibitions of MRP2 and BCRP might result in decreased excretion of their substrate drugs.

Methotrexate (MTX), a critical drug existing as anions in blood, is also a substrate of MRPs and BCRP like the conjugated metabolites [18–20]. MTX is clinically prescribed for the treatments of cancers [21,22] and autoimmune diseases, such as rheumatic arthritis and psoriasis [23–25], but with narrow therapeutic index. Nephrotoxicity and hepatoxicity were the common side effects of MTX [24,26,27], therefore, the serum concentration of MTX should be monitored for reducing the risks of adverse events. Moreover, patients treated with MTX often suffered from serious drug interactions, such as MTX-NSAIDs interactions, which were highly attributed to the inhibition of MRPs and BCRP [28,29]. Kidney is the major route for MTX elimination [30], thus any modulation on the function of renal efflux transporters like MRPs and BCRP would alter the elimination of MTX and its efficacy or toxicity. Based on the above rationale, we hypothesized that the conjugated metabolites of MN and HK might compete with MTX for the MRP2- or BCRP-mediated efflux transports and decrease the renal excretion of MTX. Therefore, this study aimed to investigate the effect of coadministration of MOC on the pharmacokinetics of MTX and relevant mechanisms.

2. Materials and methods

2.1. Chemicals and reagents

MOC was obtained from a Chinese drugstore (Taichung, Taiwan) and identified through visual inspection and microscopic examination by Dr. Yu-Chi Hou. A voucher specimen (CMU-P-1905-13) was deposited in China Medical University. MN and HK were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). MTX (25 mg/mL) was supplied by Wyeth Pharma Gmbh (Wolfratshausen, Germany). Mitoxantrone (MXR) was obtained from Enzo Life Sciences, Inc. (Farmingdale, NY, USA). Butylparaben was obtained from Sigma (St. Louis, MO, USA). Dulbecco’s Modified Eagle Medium (DMEM), Hank’s Buffered Salt Solution (HBSS) and 5-chloromethylfluorescein diacetate (CMFDA) were purchased from Invitrogen (Grand Island, NY, USA). Acetonitrile and methyl alcohol (MeOH) were supplied by Mallinckrodt Baker, Inc. (Phillipsburg, NJ, USA). Milli-Q plus water (Millipore, Bedford, MA, USA) was used for all processes.

2.2. Preparation and characterization of MOC

The preparation of MOC was modified from our previous study [31]. Briefly, crude drugs of MOC (100 g) were immersed with 4000 mL of water. The other procedures were the same as previous described. Finally, the filtrate was concentrated to make 200 mL to afford a concentration of 0.5 g/mL of MOC decoction. Then, 500 μL of MOC was mixed with 500 μL of butyl paraben solution (40 μg/mL in MeOH as internal standard). After vortexed and centrifuged, 20 μL of the supernatant was subjected to HPLC analysis. The HPLC apparatus included one pump (LC-10AT; Shimadzu, Japan), an UV detector (SPD-10A; Shimadzu, Japan), an autosampler (Series 200, PerkinElmer, USA), and a RP-C18 column (4.6 × 250 mm, 5 μm; Alltech Associates Inc., USA). The mobile phase was acetonitrile/0.1% phosphoric acid (60:40) and run isocratically. The detection wavelength was set at 290 nm and the flow rate was 1.0 mL/min.

2.3. Animals and drug administration

Male Sprague–Dawley rats (350–450 g) were purchased from BioLASCO Taiwan Co., Ltd. (Yi-Lan, Taiwan) and housed in a 12-h light–dark cycle, constant temperature environment at the Animal Center of ChinaMedical University (Taichung, Taiwan) prior to study. The study was conducted in accordance with the recommendations by “The Guidebook for the Care and Use of Laboratory Animals” published by the Chinese Society for the Laboratory Animal Science, Taiwan, ROC. This protocol (CMUIACUC-2019-127-2) was approved by the Institutional Animal Care and Use Committee (IACUC), China Medical University (Taichung, Taiwan).

Rats were randomly divided into four groups and a parallel study was conducted. Before experiment, rats were fasted overnight, but drinking water was allowed ad libitum. Food was supplied 3 h after drug administration. The 1st group (n = 6) was orally given MTX (5.0 mg/kg) alone with an equal volume of water as MOC. The 2nd groups (n = 6) and 3rd groups (n = 6) were concomitantly administered with 2.0 g/kg and 4.0 g/kg of MOC at 0.5 h before MTX (5.0 mg/kg), respectively. The dose selection was based on the daily dosage of MOC in the 4th Taiwan Herbal Pharmacopeia [32] and the USFDA 2005 guideline for “Conversion of Animal Doses to Human Equivalent Doses” [33]. The 4th group (n = 5) was orally administered 2.0 g/kg of MOC thrice daily for two days and the 7th dose was given at 0.5 h before MTX.

2.4. Blood collection and the determination of MTX in serum

The blood samples (0.5 mL) were collected via the tail vein at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h. Then, the serum concentration of MTX was measured by a fluorescence polarization immunoassay (Abbott, Abbott Park, IL, USA). All the procedures, calibration curve and validation were conducted according to the manufacturer’s instructions.

2.5. Cell line, culture conditions and MTT assay for cell viability

Madin–Darby canine kidney type II wild-type (WT) cells and two transfected cells with over-expression of MRP2 (MDCKII-MRP2) and BCRP (MDCKII-BCRP) were all kindly obtained from Professor Dr. Piet Borst (Netherlands Cancer Institute, Amsterdam, Netherlands) [34]. Cells were grown in DMEM medium supplemented with 10% of fetal bovine serum (Biological Industries Inc., Kibbutz, Beit Haemek, Israel), 1% of penicillin-streptomycin-glutamine (Invitrogen, Grand Island, NY, USA) at 37 °C in a humidified incubator containing 5% CO2 [31,34]. Furthermore, the effects of tested agents on the viability of MDCKII-WT, MDCKII-MRP2 and MDCKII-BCRP cells were evaluated by MTT assay [35] with minor modification [31].

2.6. Preparation of the serum metabolites of MOC (MOCM)

Three rats were orally administered two doses of MOC (2.0 g/kg) with an interval of 30 min, then the blood was collected at 30 min after the second dose. In parallel, the blood was collected from another three rats untreated with MOC to prepare the serum as blank control. Other procedures were the same as our previous study [31].

2.7. Effects of MOC, MN, HK and MOCM on MRP2 activity

The effects of MOC, MN, HK and MOCM on the function of MRP2 were evaluated by using MDCKII-WT and MDCKII-MRP2 cells [31,36], respectively, and CMFDA (1 μM) was used as a fluorescent probe for evaluating the activity of MRP2. MK 571 (Enzo Life Sciences, Inc, Farmingdale, NY, USA) was used as a positive control of MRP2. Briefly, MDCKII-WT cells (1 × 105 cells/well) were incubated with the tested agents at 37 °C for 30 min. The fluorescence was set at 485/528 nm (excitation/emission). The relative intracellular accumulation of glutathione-methylfluorescein (GSMF, a metabolite of CMFDA), a fluorescent substrate of MRP2, was calculated by comparing with that of control. Besides, before experiments, MOCM sample was re-dissolved in 1 mL of water to afford a solution with 10-fold serum concentration and filtered with 0.2-μm pore size filter (Sartorius Stedim Biotech Gmbh, Gottingen, Germany). Furthermore, 10-fold serum concentration of MOCM was diluted with HBSS to afford a series solution of 1-fold and 1/2-fold serum concentration. Then, MDCKII-MRP2 cell suspension (5 × 105 cells/tube) was co-incubated with test agents and CMFDA at 37 °C for 30 min. The intracellular accumulation of GSMF was monitored by a FACScan flow cytometer (Becton Dickinson Immunocytometry Systems, San Jose, CA) equipped with a standard argon laser. All data of MOCM were obtained after correction with the correspondent concentration of blank serum control. The transport studies were performed in triplicates.

2.8. Effects of MOC and MOCM on BCRP activity

The effect of MOC and MOCM on the function of BCRP was evaluated by using MDCKII-BCRP cells [16,31]. MXR (5 μM) was used as a probe for evaluating the activity of BCRP and Ko143 (Enzo Life Sciences, Inc, Farmingdale, NY, USA) was used as a positive control of BCRP. Briefly, MDCKII-BCRP cells (1 × 105 cells/well) were incubated with the tested agents at 37 °C for 2 h. After the cells were collected and lysed, the fluorescence of MXR was monitored at 607/684 nm (excitation/emission). On other hand, MDCKII-BCRP cell suspension (5 × 105 cells/tube) was pre-incubated with tested agents at 37 °C for 15 min. MXR was co-incubated for 30 min. The intracellular accumulation of MXR was determined by a FACScan flow cytometer equipped with a standard HeNe laser. All data of MOCM were obtained after correction with the correspondent concentration of blank serum control. The transport studies were performed in triplicates.

2.9. Data analysis

Pharmacokinetic parameters were calculated by using noncompartment model with the aid of Phoenix WinNonlin (version 8.1, Pharsight Corp., NC, USA). The differences of pharmacokinetic parameters of rats among four treatments were analyzed by one-way ANOVA with Scheffe test, and unpaired Student’s t-test was used for cell studies, taking P < 0.05 as significant level.

3. Results

3.1. Characterization of MOC

The HPLC chromatogram of MOC is shown in Fig. 1. The peaks of MN and HK were satisfactorily resolved within 18 min by an isocratic elution. The calibration curves (2.0–250.0 μg/mL) of MN and HK both showed good linearities with a correlation coefficient of 0.999. The coefficients of variation of intraday and interday analysis were less than 9% and the relative errors were below 16%. The recoveries were 94–108% and 94–100% for MN and HK, respectively. The quantitation results showed that MOC (0.5 g/mL) contained 0.9 and 0.5 μmol/mL of MN and HK, respectively. Accordingly, a dose of 2.0 g/kg of MOC contained 3.6 and 2.0 μmol/kg of MN and HK, and a dose of 4.0 g/kg of MOC contained 7.2 and 4.0 μmol/kg of MN and HK, respectively.

Fig. 1.

Fig. 1

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HPLC chromatogram of MN, HK and butyl paraben (internal standard) in MOC.

3.2. Effect of coadministration of MOC on MTX pharmacokinetics in rats

The serum MTX profiles after oral dosing of MTX alone and coadministrations with single dose (2.0 g/kg and 4.0 g/kg) and the 7th dose (2.0 g/kg) of MOC are shown in Fig. 2(A). The pharmacokinetic parameters of MTX after four treatments are listed in Table 1. After coadministration with single dose of 2.0 g/kg of MOC, the AUC0-t and MRT of MTX was significantly increased by 352% and 308%, respectively. While 4.0 g/kg of MOC was coadministered, the AUC0-t and MRT of MTX was significantly increased by 362% and 291%, respectively. After coadministration of the 7th dose of MOC at 2.0 g/kg, the AUC0-t and MRT of MTX was significantly increased by 461% and 334%, respectively.

Fig. 2.

Fig. 2

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(A): Mean (± S.E.) serum concentration–time profiles of MTX after oral doing of MTX alone (5.0 mg/kg) (○, n = 6) and coadministration with single dose of 2.0 g/kg (■, n = 6), 4.0 g/kg (▼, n = 6) and the 7th dose of 2.0 g/kg (▲, n = 5) of MOC and (B): the semi-log diagram of (A).

Table 1.

Comparison of pharmacokinetic parameters of MTX after oral administration of 5.0 mg/kg of MTX alone (n = 6) and coadministered with 2.0 g/kg (n = 6), 4.0 g/kg (n = 6) and seven doses of 2.0 g/kg (n = 5) of MOC.

Parameters Treatment
MTX + water MTX + MOC (2.0 g/kg) MTX + MOC (4.0 g/kg) MTX + MOC (2.0 g/kg, 7th dose)
Cmax 0.2 ± 0.03 0.3 ± 0.01 0.2 ± 0.03 0.3 ± 0.04
AUC0-t 44.6 ± 5.0a 201.5 ± 39.2b (+352%) 206.8 ± 35.9b (+362%) 250.2 ± 31.2b (+461%)
MRT 287.6 ± 26.4a 1174.1 ± 255.8b (+308%) 1124.1 ± 189.6b (+291%) 1248.8 ± 242.3b (+334%)
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Values are means ± S.E.

Mean in a row without a common superscript differ, P < 0.05.

A mean with a symbol “a” was significantly different from a mean with a symbol “b”, and the symbol “ab” means that this treatment group show no significant difference when compared to other groups.

Tmax (min): time to reach peak serum concentration.

Cmax (μmol·mL−1): peak serum concentration.

AUC0-t (μmol·min·mL−1): area under the blood concentration–time curve.

MRT (min): mean residence time.

3.3. Cell viability assay

MTT assay indicated that 150 μM of MN and HK in MDCKII-WT cells, 100 μM of MN and HK in MDCKII-BCRP cells and 1-fold serum concentration of MOCM in both MDCKII-MRP2 and MDCKII-BCRP cells all exhibited no toxic effects on the cell viability (data not shown).

3.4. Effects of MOC, MN, HK and MOCM on MRP2 activity

The effects of MOC, MN and HK on the intracellular accumulation of GSMF in MDCKII-WT cells are shown in Fig. 3(A) and (B). The results revealed that MOC at 0.2, 1 and 5 mg/mL did not influence the intracellular accumulation of GSMF. As a positive control of MRP2 inhibitor, MK571 significantly increased the accumulation of GSMF by 203%. MN at 50 μM significantly increased the accumulation of GSMF by 137%; HK at 25 and 50 μM significantly increased the accumulation of GSMF by 34% and 75%, respectively. As a positive control of MRP2 inhibitor, MK 571 increased the accumulation of GSMF by 331%.

Fig. 3.

Fig. 3

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Effects of (A) MOC (mg/mL), (B) MN (μM), HK (μM) and MK 571 (50 μM, a specific inhibitor of MRP2) on the intracellular accumulation of GSMF (mean ± S.D.) in MDCKII-WT cells. (C) Effects of MOCM (1- and 1/2-fold serum concentration) and MK 571 (100 μM, spiked in blank serum) on the intracellular accumulation of GSMF (mean ± S.D.) in MDCKII-MRP2 cells. (*P < 0.05, **P < 0.01, ***P < 0.001).

The effect of MOCM on the accumulation of GSMF in MDCKII-MRP2 cells is shown in Fig. 3(C). The results indicated that at 1-fold serum concentration, MOCM significantly increased the accumulation of GSMF by 17%. As a positive control of MRP2 inhibitor, MK 571 increased the accumulation of GSMF by 72%.

3.5. Effects of MOC and MOCM on BCRP activity

The effects of MOC and MOCM on the intracellular accumulation of MXR in MDCKII-BCRP cells are shown in Fig. 4. The results revealed that MOC at 0.2, 1 and 5 mg/mL significantly decreased the accumulation of MXR by 6%, 13% and 29%, respectively. As a positive control of BCRP inhibitor, Ko143 significantly increased by 55%.

Fig. 4.

Fig. 4

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Effects of (A) MOC (mg/mL) and Ko143 (0.25 μM, a specific inhibitor of BCRP) on the intracellular accumulation of MXR (mean ± S.D.) in MDCKII-BCRP cells. (B) MOCM (1- and 1/2-fold serum concentration) and Ko143 (0.25 μM, spiked in blank serum) on the intracellular accumulation of MXR (mean ± S.D.) in MDCKII-BCRP cells. (*P < 0.05, **P < 0.01, ***P < 0.001).

On other hand, MOCM did not influence the intracellular accumulation of MXR. As a positive control of BCRP inhibitor, Ko143 significantly increased the accumulation of MXR by 60%.

4. Discussion

The determination of MN and HK concentrations in MOC by HPLC showed that the content of MN was higher than HK, which was consistent with previous studies [37,38]. The results of MOC-MTX interaction study in rats revealed that single-dose MOC either at 2.0 or 4.0 g/kg markedly increased the AUC0-t and MRT of MTX, indicating that the oral bioavailability of MTX was greatly enhanced by the coadministration of MOC. Likewise, when rats were given the 7th dose of MOC at 2.0 g/kg before MTX, the oral bioavailability of MTX was increased in comparably great extent with the single-dose treatments. Observation of the serum profiles among four treatments revealed that the four curves in the very short absorption phase were essentially overlapping, and the post-absorption profile of control group was much lower than other three groups coadministered with MOC, indicating that either single dose or multiple doses of MOC markedly decreased the elimination of MTX. Therefore, the increased bioavailability of MTX was apparently resulted from the inhibited elimination of MTX.

Referring to relevant pharmacokinetic studies, MN and the glucuronides/sulfates of MN were existing in the serum after ingestion of MN, while after administration of HK, only the glucuronides/sulfates of HK were present in the plasma, but no parent form of HK [11,12], indicating that MN and HK underwent extensive phase II metabolism, especially HK. Accordingly, for mimicking the virtual molecules contacting with transporters at the apical membranes of liver and kidney, MOCM was prepared from the serum of rats administered with MOC. Then, MOCM was used in cell studies to evaluate the modulation effects on MRP2 and BCRP.

In recent decades, several polyphenolics and their conjugated metabolites were verified as substrates and/or inhibitors of MRPs and BCRP [31,39–41], and MTX is also a substrate of MRP2 and BCRP, therefore, MRP2 and BCRP were proposed to be involved in the mechanism of MOC-MTX interaction. Subsequently, cell lines including MDCKII-WT, MDCKII-MRP2 and MDCKII-BCRP were employed for the mechanism elucidation.

Regarding the involvement of MRP2 in this MOCM-TX interaction, cell studies showed that the intracellular accumulation of GSMF, a typical substrate of MRP2, was increased by MN, HK and MOCM, indicating that MN, HK and MOCM all inhibited the MRP2-mediated efflux transport. Based on previous pharmacokinetic findings, we could assume that the free form MN, MN glucuronides/sulfates and HK glucuronides/sulfates were the major causative molecules of MOCM in inhibitions on MRP2 [11,12]. Because MTX was predominantly eliminated via kidney, once the MRP2 on the apical membrane of kidney was inhibited by MOCM, the excretion of MTX would be reduced. On other hand, MOC did not exert influence on MRP2 activity, we speculated that beyond MN and HK, some other compositions in MOC might activate MRP2 and cancel out the inhibition effects caused by MN and HK. Taken together, we concluded that the MRP2-mediated renal excretion of MTX was inhibited by MN, MN glucuronides/sulfates and HK glucuronides/sulfates, which could in part account for the decreased elimination and enhanced systemic exposure of MTX after MOC coadministration.

Concerning the probable involvement of BCRP in this MOC-MTX interaction, our previous study found that MN and HK at concentrations of 12.5–100 μM significantly inhibited BCRP [16], conversely, this study showed that MOC slightly activated BCRP. We speculated that beyond MN and HK, some other constituents of MOC strongly activated BCRP and overwhelmed the inhibition effects caused by MN and HK. On other hand, MOCM at 1-fold serum concentration did not influence the function of BCRP. These results indicated that both MOC and MOCM did not inhibit the efflux transport of BCRP. Accordingly, we could infer that MOC ingestion did not inhibit the BCRP-mediated elimination of MTX. Therefore, BCRP was not involved in the mechanism of MOC-MTX interaction.

In brief, coadministration of MOC inhibited the MRP2-mediated renal excretion of MTX and resulted in marked increases of the systemic exposure and mean residence time of MTX. Besides, during the pharmacokinetic study, we also noticed that the mortalities of rats in the three groups coadministered with MOC were higher than that of control group. The control rats administered MTX alone all survived very well throughout the study. Apparently, the enhanced mortalities of MTX in rats was arisen from the markedly increased systemic exposure of MTX when MOC was coadministered.

In clinical settings, if patients are given low dose of MTX for treating rheumatoid arthritis or psoriasis [42–44], coadministration of MOC may lead to better efficacy. Nevertheless, when cancer patients are treated with high dose of MTX [45], the coadministration of MOC may result in serious adverse effects. Therefore, clinicians are suggested to be cautious for the blood concentration monitoring and dose adjustment of MTX when high dose of MTX is coadministered with MOC. Furthermore, the concurrent use of MOC with any critical substrate drugs of MRP2 should be avoided.

In conclusion, coadministration of MOC markedly increased the systemic exposure and mean residence time of MTX through inhibiting the MRP2-mediated renal excretion of MTX. We suggest that the concomitant use of MOC with MTX should be with great caution.

Supplementary Information

jfda-32-01-103-s001.pdf (120.3KB, pdf)

Acknowledgement

This work was supported in part by the National Science and Technology Council, Taiwan, ROC. (MOST 111-2320-B-039-048, NSTC 112-2320-B-039-028 and NSTC 112-2320-B-039-029), China Medical University, Taiwan, ROC (CMU111-MF-30).

Funding Statement

This work was supported in part by the National Science and Technology Council, Taiwan, ROC. (MOST 111-2320-B-039-048, NSTC 112-2320-B-039-028 and NSTC 112-2320-B-039-029), China Medical University, Taiwan, ROC (CMU111-MF-30)

Footnotes

Conflicts of interest: The authors declare that there are no conflicts of interest.

References

  • 1. Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT. Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther. 2011;130:157–76. doi: 10.1016/j.pharmthera.2011.01.010. [DOI] [PubMed] [Google Scholar]
  • 2. Yan R, Yu S, Liu H, Xue Z, Yang B. An HPLC-DAD method for simultaneous quantitative determination of four active hydrophilic compounds in Magnoliae officinalis cortex. J Chromatogr Sci. 2015;53:598–602. doi: 10.1093/chromsci/bmu091. [DOI] [PubMed] [Google Scholar]
  • 3. Jiang Y, Vaysse J, Gilard V, Balayssac S, Dejean S, Malet-Martino M, et al. Quality assessment of commercial Magnoliae officinalis Cortex by (1)H-NMR-based metabolomics and HPLC methods. Phytochem Anal. 2012;23:387–95. doi: 10.1002/pca.1369. [DOI] [PubMed] [Google Scholar]
  • 4. Walker JM, Maitra A, Walker J, Ehrnhoefer-Ressler MM, Inui T, Somoza V. Identification of Magnolia officinalis L. bark extract as the most potent anti-inflammatory of four plant extracts. Am J Chin Med. 2013;41:531–44. doi: 10.1142/S0192415X13500389. [DOI] [PubMed] [Google Scholar]
  • 5. Chan SS-K, Zhao M, Lao L, Fong HH, Che C-T. Magnolol and honokiol account for the anti-spasmodic effect of Magnolia officinalis in isolated Guinea pig ileum. Planta Med. 2008;74:381–4. doi: 10.1055/s-2008-1034320. [DOI] [PubMed] [Google Scholar]
  • 6. Chen CR, Zhou XZ, Luo YJ, Huang ZL, Urade Y, Qu WM. Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, induces sleep via the benzodiazepine site of GABA(A) receptor in mice. Neuropharmacology. 2012;63:1191–9. doi: 10.1016/j.neuropharm.2012.06.031. [DOI] [PubMed] [Google Scholar]
  • 7. Xu Q, Yi LT, Pan Y, Wang X, Li YC, Li JM, et al. Antide-pressant-like effects of the mixture of honokiol and magnolol from the barks of Magnolia officinalis in stressed rodents. Prog Neuro-Psychopharmacol Biol Psychiatry. 2008;32:715–25. doi: 10.1016/j.pnpbp.2007.11.020. [DOI] [PubMed] [Google Scholar]
  • 8. Mottaghi S, Abbaszadeh H. Natural lignans honokiol and magnolol as potential anticarcinogenic and anticancer agents. A comprehensive mechanistic review. Nutr Cancer. 2022;74:761–78. doi: 10.1080/01635581.2021.1931364. [DOI] [PubMed] [Google Scholar]
  • 9. Poivre M, Duez P. Biological activity and toxicity of the Chinese herb Magnolia officinalis Rehder & E. Wilson (Houpo) and its constituents. J Zhejiang Univ - Sci B. 2017;18:194. doi: 10.1631/jzus.B1600299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Bui D, Li L, Yin T, Wang X, Gao S, You M, et al. Pharmacokinetic and metabolic profiling of key active components of dietary supplement Magnolia officinalis extract for prevention against oral carcinoma. J Agric Food Chem. 2020;68:6576–87. doi: 10.1021/acs.jafc.0c01475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Lin SP, Tsai SY, Lee Chao PD, Chen YC, Hou YC. Pharmacokinetics, bioavailability, and tissue distribution of magnolol following single and repeated dosing of magnolol to rats. Planta Med. 2011;77:1800–5. doi: 10.1055/s-0030-1271159. [DOI] [PubMed] [Google Scholar]
  • 12. Wang JJ, Miao XL, Chen JY, Chen Y. The pharmacokinetics and tissue distribution of honokiol and its metabolites in rats. Eur J Drug Metab Pharmacokinet. 2016;41:587–94. doi: 10.1007/s13318-015-0281-6. [DOI] [PubMed] [Google Scholar]
  • 13. Keppler D. Uptake and efflux transporters for conjugates in human hepatocytes. Methods Enzymol. 2005;400:531–42. doi: 10.1016/S0076-6879(05)00029-7. [DOI] [PubMed] [Google Scholar]
  • 14. Liu YH, Di YM, Zhou ZW, Mo SL, Zhou SF. Multidrug resistance-associated proteins and implications in drug development. Clin Exp Pharmacol Physiol. 2009;37:115–20. doi: 10.1111/j.1440-1681.2009.05252.x. [DOI] [PubMed] [Google Scholar]
  • 15. Järvinen E, Deng F, Kiander W, Sinokki A, Kidron H, Sjöstedt N. The role of uptake and efflux transporters in the disposition of glucuronide and sulfate conjugates. Front Pharmacol. 2022;12:802539. doi: 10.3389/fphar.2021.802539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Yu CP, Li PY, Chen SY, Lin SP, Hou YC. Magnolol and honokiol inhibited the function and expression of BCRP with mechanism exploration. Molecules. 2021;26:7390. doi: 10.3390/molecules26237390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Choudhuri S, Klaassen CD. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int J Toxicol. 2006;25:231–59. doi: 10.1080/10915810600746023. [DOI] [PubMed] [Google Scholar]
  • 18. Vlaming ML, Pala Z, van Esch A, Wagenaar E, van Tellingen O, de Waart DR, et al. Impact of Abcc2 (Mrp2) and Abcc3 (Mrp3) on the in vivo elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate. Clin Cancer Res. 2008;14:8152–60. doi: 10.1158/1078-0432.CCR-08-1609. [DOI] [PubMed] [Google Scholar]
  • 19. Vlaming ML, van Esch A, van de Steeg E, Pala Z, Wagenaar E, van Tellingen O, et al. Impact of abcc2 [multidrug resistance-associated protein (MRP) 2], abcc3 (MRP3), and abcg2 (breast cancer resistance protein) on the oral pharmacokinetics of methotrexate and its main metabolite 7-hydroxymethotrexate. Drug Metab Dispos. 2011;39:1338–44. doi: 10.1124/dmd.111.038794. [DOI] [PubMed] [Google Scholar]
  • 20. Liu X. Transporter-mediated drug-drug interactions and their significance. Adv Exp Med Biol. 2019;1141:241–91. doi: 10.1007/978-981-13-7647-4_5. [DOI] [PubMed] [Google Scholar]
  • 21. Abolmaali SS, Tamaddon AM, Dinarvand R. A review of therapeutic challenges and achievements of methotrexate delivery systems for treatment of cancer and rheumatoid arthritis. Cancer Chemother Pharmacol. 2013;71:1115–30. doi: 10.1007/s00280-012-2062-0. [DOI] [PubMed] [Google Scholar]
  • 22. Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer. 1978;41:36–51. doi: 10.1002/1097-0142(197801)41:1<36::aid-cncr2820410108>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  • 23. Dogra S, Mahajan R. Systemic methotrexate therapy for psoriasis: past, present and future. Clin Exp Dermatol. 2013;38:573–88. doi: 10.1111/ced.12062. [DOI] [PubMed] [Google Scholar]
  • 24. Montaudie H, Sbidian E, Paul C, Maza A, Gallini A, Aractingi S, et al. Methotrexate in psoriasis: a systematic review of treatment modalities, incidence, risk factors and monitoring of liver toxicity. J Eur Acad Dermatol Venereol. 2011;25(Suppl 2):12–8. doi: 10.1111/j.1468-3083.2011.03991.x. [DOI] [PubMed] [Google Scholar]
  • 25. Bourre-Tessier J, Haraoui B. Methotrexate drug interactions in the treatment of rheumatoid arthritis: a systematic review. J Rheumatol. 2010;37:1416–21. doi: 10.3899/jrheum.090153. [DOI] [PubMed] [Google Scholar]
  • 26. Keysser G. Methotrexate toxicity. Myths and facts. Z Rheumatol. 2011;70:108–13. doi: 10.1007/s00393-010-0687-0. [DOI] [PubMed] [Google Scholar]
  • 27. Tsukada T, Nakano T, Miyata T, Sasaki S. Life-threatening gastrointestinal mucosal necrosis during methotrexate treatment for rheumatoid arthritis. Case Rep Gastroenterol. 2013;7:470–5. doi: 10.1159/000356817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Lagas JS, van der Kruijssen CM, van de Wetering K, Beijnen JH, Schinkel AH. Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of multidrug resistance protein 2 (ABCC2)-mediated drug transport by diclofenac and benzbromarone. Drug Metab Dispos. 2009;37:129–36. doi: 10.1124/dmd.108.023200. [DOI] [PubMed] [Google Scholar]
  • 29. El-Sheikh AA, van den Heuvel JJ, Koenderink JB, Russel FG. Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport. J Pharmacol Exp Therapeut. 2007;320:229–35. doi: 10.1124/jpet.106.110379. [DOI] [PubMed] [Google Scholar]
  • 30. Hamed KM, Dighriri IM, Baomar AF, Alharthy BT, Alenazi FE, Alali GH, et al. Overview of methotrexate toxicity: a comprehensive literature review. Cureus. 2022:14. doi: 10.7759/cureus.29518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Yu CP, Hsieh YC, Shia CS, Hsu PW, Chen JY, Hou YC, et al. Increased systemic exposure of methotrexate by a polyphenol-rich herb via modulation on efflux transporters multidrug resistance-associated protein 2 and breast cancer resistance protein. J Pharm Sci. 2016;105:343–9. doi: 10.1016/j.xphs.2015.11.031. [DOI] [PubMed] [Google Scholar]
  • 32.Taiwan Herbal Pharmacopeia. 4th Edition Committee Taiwan herbal Pharmacopeia. 4th ed. Department of Chinese Medicine and Pharmacy, Ministry of Health and Welfare; 2022. English version. [Google Scholar]
  • 33.Food and Drug Administration. Guidance for Industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Vol. 7. Center for Drug Evaluation and Research CDER; 2005. p. 0.001. [Google Scholar]
  • 34. Xiao L, Yi T, Chen M, Lam CWK, Zhou H. A new mechanism for increasing the oral bioavailability of scutellarin with Cremophor EL: activation of MRP3 with concurrent inhibition of MRP2 and BCRP. Eur J Pharmaceut Sci. 2016;93:456–67. doi: 10.1016/j.ejps.2016.08.054. [DOI] [PubMed] [Google Scholar]
  • 35. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  • 36. Hsu PW, Shia CS, Wu CT, Chang NW, Chao PL, Hou YC. Noni increased the systemic exposure of methotrexate in rats through inhibition on multi-drug resistance protein 2 and breast cancer resistance protein (BCRP) J Funct Foods. 2013;5:1414–20. [Google Scholar]
  • 37. Wang RQ, Ge X, Chen X, Hu S, Yang L, Li D, et al. Ballpoint tip-protected oil-in-salt liquid-phase microextraction with high performance liquid chromatography for the determination of magnolol and honokiol from cortex Magnoliae officinalis. Instrum Sci Technol. 2020;48:254–68. [Google Scholar]
  • 38. Tsai TH, Chen CF. Identification and determination of honokiol and magnolol from Magnolia officinalis by high-performance liquid chromatography with phtodiode-array UV detection. J Chromatogr A. 1992;598:143–6. [Google Scholar]
  • 39. Zheng L, Zhu L, Zhao M, Shi J, Li Y, Yu J, et al. In vivo exposure of kaempferol is driven by phase II metabolic enzymes and efflux transporters. AAPS J. 2016;18:1289–99. doi: 10.1208/s12248-016-9951-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Brand W, Oosterhuis B, Krajcsi P, Barron D, Dionisi F, Van Bladeren PJ, et al. Interaction of hesperetin glucuronide conjugates with human BCRP, MRP2 and MRP3 as detected in membrane vesicles of overexpressing baculovirus-infected Sf9 cells. Biopharm Drug Dispos. 2011;32:530–5. doi: 10.1002/bdd.780. [DOI] [PubMed] [Google Scholar]
  • 41. Wang L, Sun R, Zhang Q, Luo Q, Zeng S, Li X, et al. An update on polyphenol disposition via coupled metabolic pathways. Expert Opin Drug Met. 2019;15:151–65. doi: 10.1080/17425255.2019.1559815. [DOI] [PubMed] [Google Scholar]
  • 42. Coates LC, Merola JF, Grieb SM, Mease PJ, Duffin KC. Methotrexate in psoriasis and psoriatic arthritis. J Rheumatol Suppl. 2020;96:31–5. doi: 10.3899/jrheum.200124. [DOI] [PubMed] [Google Scholar]
  • 43. Solomon DH, Glynn RJ, Karlson EW, Lu F, Corrigan C, Colls J, et al. Adverse effects of low-dose methotrexate: a randomized trial. Ann Intern Med. 2020;172:369–80. doi: 10.7326/M19-3369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Lucas CJ, Dimmitt SB, Martin JH. Optimising low-dose methotrexate for rheumatoid arthritis—a review. Br J Clin Pharmacol. 2019;85:2228–34. doi: 10.1111/bcp.14057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Song Z, Hu Y, Liu S, Wang G, Zhai S, Zhang X, et al. Medication therapy of high-dose methotrexate: an evidence-based practice guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. Br J Clin Pharmacol. 2022;88:2456–72. doi: 10.1111/bcp.15134. [DOI] [PubMed] [Google Scholar]

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