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Tetrahydrofurofuranoid Lignans, Eudesmin, Fargesin, Epimagnolin A

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Tetrahydrofurofuranoid Lignans, Eudesmin, Fargesin, Epimagnolin A pharmaceutics Article Tetrahydrofurofuranoid Lignans, Eudesmin, Fargesin, Epimagnolin A, Magnolin, and Yangambin Inhibit UDP-Glucuronosyltransferase 1A1 and 1A3 Activities in Human Liver Microsomes Ria Park 1,†, Eun Jeong Park 1,†, Yong-Yeon Cho 1, Joo Young Lee 1 , Han Chang Kang 1 , Im-Sook Song 2 and Hye Suk Lee 1,* 1 College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea; [email protected] (R.P.); [email protected] (E.J.P.); [email protected] (Y.-Y.C.); [email protected] (J.Y.L.); [email protected] (H.C.K.) 2 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-2-2164-4061; Fax: +82-32-342-2013 † These authors contributed equally to this work. Abstract: Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin are tetrahydrofurofuranoid lignans with various pharmacological activities found in Magnoliae Flos. The inhibition potencies 0 of eudesmin, fargesin, epimagnolin A, magnolin, and yangambin on six major human uridine 5 - diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes were evaluated Citation: Park, R.; Park, E.J.; Cho, using liquid chromatography–tandem mass spectrometry and cocktail substrates. Eudesmin, fargesin, Y.-Y.; Lee, J.Y.; Kang, H.C.; Song, I.-S.; epimagnolin A, magnolin, and yangambin inhibited UGT1A1 and UGT1A3 activities, but showed Lee, H.S. Tetrahydrofurofuranoid negligible inhibition of UGT1A4, UGT16, UGT1A9, and UGT2B7 activities at 200 µM in pooled Lignans, Eudesmin, Fargesin, human liver microsomes. Moreover, eudesmin, fargesin, epimagnolin A, magnolin, and yangambin Epimagnolin A, Magnolin, and Yangambin Inhibit noncompetitively inhibited UGT1A1-catalyzed SN38 glucuronidation with Ki values of 25.7, 25.3, 3.6, UDP-Glucuronosyltransferase 1A1 26.0, and 17.1 µM, respectively, based on kinetic analysis of UGT1A1 inhibition in pooled human and 1A3 Activities in Human Liver liver microsomes. Conversely, the aforementioned tetrahydrofurofuranoid lignans competitively Microsomes. Pharmaceutics 2021, 13, inhibited UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation with 39.8, 24.3, 15.1, 187. https://doi.org/10.3390/ 37.6, and 66.8 µM, respectively in pooled human liver microsomes. These in vitro results suggest pharmaceutics13020187 the necessity of evaluating whether the five tetrahydrofurofuranoid lignans can cause drug–drug interactions with UGT1A1 and UGT1A3 substrates in vivo. Academic Editors: Charles M. Heard and Maria Rosaria Lauro Keywords: eudesmin; fargesin; epimagnolin A; magnolin; yangambin; human liver microsomes; Received: 6 December 2020 UDP-glucuronosyltransferase Accepted: 28 January 2021 Published: 1 February 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in published maps and institutional affil- Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin (Figure1) are the iations. pharmacologically active tetrahydrofurofuranoid lignans found in Magnolia denudata Desrousseaux, M. fargesii Cheng (family: Magnoliaceae), and Zanthoxylum armatum DC (family: Rutaceae) [1–5]. These lignans possess anti-inflammatory activity through the inhibitory effects on 5-lipoxygenase and nitric oxide synthase [5–9] and antitumor activ- ity [10–12]. In addition to the anti-inflammatory and antitumor activity of tetrahydrofurofu- Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. ranoid lignans, eudesmin showed bactericidal effect on Helicobacter pylori reference strain This article is an open access article 26,695 and suppressed inflammatory and immune responses in Helicobacter pylori-infected distributed under the terms and mice [13]. Fargesin exhibits additional biological activities, including cardioprotective ef- conditions of the Creative Commons fect in rats with ischemia/reperfusion injury [14] and lipid lowering and hypoglycemic Attribution (CC BY) license (https:// effects in high-fat diet-induced obese mice [15], and antihypertensive effects in 2K1C hy- creativecommons.org/licenses/by/ pertensive rats [16]. Magnolin also ameliorates contrast-induced nephropathy in rats via 4.0/). anti-oxidation and anti-apoptosis [17]. Pharmaceutics 2021, 13, 187. https://doi.org/10.3390/pharmaceutics13020187 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, 2 of 14 tective effect in rats with ischemia/reperfusion injury [14] and lipid lowering and hypo- glycemic effects in high-fat diet-induced obese mice [15], and antihypertensive effects in 2K1C hypertensive rats [16]. Magnolin also ameliorates contrast-induced nephropathy in Pharmaceutics 2021, 13, 187 2 of 13 rats via anti-oxidation and anti-apoptosis [17]. FigureFigure 1. 1. ChemicalChemical structures structures of of ( (AA)) eudesmin, eudesmin, ( (BB)) fargesin, fargesin, ( (CC)) epimagnolin epimagnolin A, A, ( (D)) magnolin, magnolin, and ( E) yangambin. TheThe ethanol ethanol extract extract of of the the dried dried flower flower buds buds of M. of fargesiiM. fargesii (encoded(encoded as NDC-052 as NDC-052 con- tainedcontained eudesmin, eudesmin, fargesin, fargesin, epimagnolin epimagnolin A, magnol A, magnolin,in, and yangambin and yangambin as 4.1, as 3.4, 4.1, 11.9, 3.4, 21.5, 11.9, and21.5, 9.1%, and respectively, 9.1%, respectively, as determined as determined by the LC-APCI-MS/MS by the LC-APCI-MS/MS method [18]) method has [been18]) hasde- been developed as an effective alternative or complement to standard asthma therapy veloped as an effective alternative or complement to standard asthma therapy based on based on their biological activities [19]. Consequently, taking NDC-052 (600 mg/day for their biological activities [19]. Consequently, taking NDC-052 (600 mg/day for 8 weeks per 8 weeks per oral) in adult asthmatic patients was safe and tolerated [19]. The add-on oral) in adult asthmatic patients was safe and tolerated [19]. The add-on therapy of NDC- therapy of NDC-052 (600 mg/day for 8 weeks per oral) with inhaled corticosteroids in 052 (600 mg/day for 8 weeks per oral) with inhaled corticosteroids in asthmatic patients asthmatic patients had a beneficial effect on asthma control [19]. The pharmacokinet- had a beneficial effect on asthma control [19]. The pharmacokinetics of herbal constituents ics of herbal constituents in rats have been investigated in addition to their biological in rats have been investigated in addition to their biological activities. Eudesmin, yangam- activities. Eudesmin, yangambin, epimagnolin A, fargesin, and magnolin were identi- bin, epimagnolin A, fargesin, and magnolin were identified in rat plasma following oral fied in rat plasma following oral administration (5.5–22 mg/kg) of NDC-052 to rats [18]. administration (5.5–22 mg/kg) of NDC-052 to rats [18]. The area under the plasma concen- The area under the plasma concentration curve (AUC) and maximum plasma concen- tration curve (AUC) and maximum plasma concentration (Cmax) values of eudesmin, tration (Cmax) values of eudesmin, yangambin, and epimagnolin linearly increased with yangambin, and epimagnolin linearly increased with dose increase [18]. However, AUC dose increase [18]. However, AUC and Cmax values of fargesin and magnolin were not andincreased Cmax values with dose of fargesin proportionality, and magnolin suggesting were thenot nonlinearincreased pharmacokineticwith dose proportionality, properties suggesting the nonlinear pharmacokinetic properties of fargesin and magnolin [18]. Ad- of fargesin and magnolin [18]. Additionally, the AUC and Cmax values of magnolin in ditionally,rats were 7568 the AUC± 1085 and ng C·h/mLmax valuesand 2493of magnolin± 513 ng/mL, in ratsrespectively, were 7568 ± when1085 ng·h/mL administered and 2493NDC-052 ± 513 (22.2 ng/mL, mg/kg respectively, containing when 4 mg/kg admi ofnistered magnolin) NDC-052 [20] and (22.2 had mg/kg similar containing results with 4 mg/kg of magnolin) [20] and had similar results with the previous report [18]. However, the previous report [18]. However, the AUC and Cmax values of magnolin in rats were the3630 AUC± 581 and ng C·h/mLmax valuesand 1340of magnolin± 113 ng/mL, in ratsrespectively, were 3630 ± when581 ng·h/mL administered and 1340 magnolin ± 113 ng/mL,alone (4 respectively, mg/kg) [21 ].when These administered results suggested magnol thein alone possibility (4 mg/kg) of drug [21]. interactions These results among sug- gestedthe constituents the possibility of herbal of drug drugs. interactions among the constituents of herbal drugs. TheThe herb-drugherb-drug interactionsinteractions among among the the herbal herbal drugs drugs (e.g., (e.g.,Hypericum Hypericum perforatum perforatum, Ginkgo, Ginkgobiloba, Camelliabiloba, Camellia sinensis sinensis, Glycyrrhiza, Glycyrrhiza glabra ,glabraAllium, Allium sativum sativum, Coptis, Coptis chinensis chinensis, and, Silybumand Si- lybummarianum marianum) and their) and constituents their constituents via the inhibitionvia the inhibition or induction or induction of major of drug-metabolizing major drug-me- tabolizingenzymes, cytochromeenzymes, cytochrome P450 (CYP) andP450 uridine (CYP) 50 -diphosphoand uridine (UDP)-glucuronosyltransferase 5′-diphospho (UDP)-glucu- ronosyltransferase(UGT) have been reported(UGT) have [22– been27]. Thus,reported evaluating [22–27]. theThus,in evaluating vitro inhibitory the in effects vitro inhib- of the itoryactive effects components of the active of herbal components drugs on of human herbal
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