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Modulation of Rat Hepatic CYP1A and 2C Activity by Honokiol and Magnolol: Differential Effects on Phenacetin and Diclofenac Pharmacokinetics in Vivo

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Modulation of Rat Hepatic CYP1A and 2C Activity by Honokiol and Magnolol: Differential Effects on Phenacetin and Diclofenac Pharmacokinetics in Vivo molecules Article Modulation of Rat Hepatic CYP1A and 2C Activity by Honokiol and Magnolol: Differential Effects on Phenacetin and Diclofenac Pharmacokinetics In Vivo Sang-Bum Kim 1,2, Kyu-Sang Kim 2, Heon-Min Ryu 2, Seong-Ho Hong 3, Bo-Kyoung Kim 1, Dae-Duk Kim 2, Jin Woo Park 4,* and In-Soo Yoon 5,* ID 1 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea; [email protected] (S.-B.K.); [email protected] (B.-K.K.) 2 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea; [email protected] (K.-S.K.); [email protected] (H.-M.R.); [email protected] (D.-D.K.) 3 Biomedicine Lab, CKD Research Institute, Gyeonggi 16995, Korea; [email protected] 4 Department of Pharmacy, College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Korea 5 Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea * Correspondence: [email protected] (J.W.P.); [email protected] (I.-S.Y.); Tel.: +82-61-450-2704 (J.W.P.); +82-51-510-2806 (I.-S.Y.) Received: 24 April 2018; Accepted: 16 June 2018; Published: 17 June 2018 Abstract: Honokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol) and magnolol (4-Allyl-2-(5-allyl-2-hydroxy-phenyl)phenol) are the major active polyphenol constituents of Magnolia officinalis (Magnoliaceae) bark, which has been widely used in traditional Chinese medicine (Houpu Tang) for the treatment of various diseases, including anxiety, stress, gastrointestinal disorders, infection, and asthma. The aim of this study was to investigate the direct effects of honokiol and magnolol on hepatic CYP1A and 2C-mediated metabolism in vitro using rat liver microsomes and in vivo using the Sprague-Dawley rat model. Honokiol and magnolol inhibited in vitro CYP1A activity (probe substrate: phenacetin) more potently than CYP2C activity (probe substrate: diclofenac): The mean IC50 values of honokiol for the metabolism of phenacetin and diclofenac were 8.59 µM and 44.7 µM, while those of magnolol were 19.0 µM and 47.3 µM, respectively. Notably, the systemic exposure (AUC and Cmax) of phenacetin, but not of diclofenac, was markedly enhanced by the concurrent administration of intravenous honokiol or magnolol. The differential effects of the two phytochemicals on phenacetin and diclofenac in vivo pharmacokinetics could at least be partly attributed to their lower IC50 values for the inhibition of phenacetin metabolism than for diclofenac metabolism. In addition, the systemic exposure, CL, and Vss of honokiol and magnolol tended to be similar between the rat groups receiving phenacetin and diclofenac. These findings improve our understanding of CYP-mediated drug interactions with M. officinalis and its active constituents. Keywords: honokiol; magnolol; Magnolia officinalis; CYP1A; CYP2C; rat; pharmacokinetics 1. Introduction The past two decades have seen a significant increase in the utilization of herbal extract formulations to complement prescription drugs administered for the prevention and treatment of disease [1]. Two independent national surveys have previously shown that the 12-month prevalence Molecules 2018, 23, 1470; doi:10.3390/molecules23061470 www.mdpi.com/journal/molecules Molecules 2018, 23, 1470 2 of 12 Molecules 2018, 23, x FOR PEER 2 of 12 of herbal medicine use was 26.3% in England [2] and 18.9% in the United States [3]. Patients mainly tendtend to to consume consume herbal herbal medicine medicine owing owing to to dissatisfaction dissatisfaction with with the the efficacy efficacy of of prescription prescription drugs, drugs, and/orand/or the the misconception thatthat herbs herbs are are ‘natural’ ‘natural’ and and thus safer,thus safer, than prescription than prescription drugs [4 ].drugs However, [4]. However,herbal extract herbal products extract products contain variouscontain activevarious phytochemicals, active phytochemicals, some of some which of which are cleared are cleared by the bycytochrome the cytochrome P450 (CYP) P450 isozymes(CYP) isozymes responsible respons forible the metabolismfor the metabolism of most prescriptionof most prescription drugs [5 ].drugs Thus, [CYP-based5]. Thus, CYP herb-drug-based herb interactions-drug interactions are inevitable, are inevitable, yet the CYP-modulating yet the CYP-modulating potential andpotential the associated and the associatedin vivo pharmacokinetic in vivo pharmacokinetic consequences consequences of many herbal of extracts many andherbal their extracts active constituents and their remainactive constituentsunexplored, remain necessitating unexplored, further necessitating investigation further [6]. investigation [6]. MagnoliaMagnolia officinalis officinalis (Magnoliaceae)(Magnoliaceae) isis mainly mainly found found in in East East Asia, Asia, and and its barkits bark has has been been widely widely used usedin traditional in traditional Chinese Chinese medicine medicine (Houpu (Houpu Tang) Tang) for the for treatment the treatment of various of various diseases, diseases, including including anxiety, anxiety,stress, gastrointestinal stress, gastrointestinal disorders, disorders, infection, infection, and asthma and [7 ].asthmaM. officinalis [7]. M.bark officinalis extract isbark commercially extract is commerciallavailable asy a available dietary supplement as a dietary in powdersupplement or capsule in powder form [8or]. Moreover,capsule form the supercritical[8]. Moreover, carbon the supercriticaldioxide extract carbon of M. dioxide officinalis extractbark is of added M. officinalis to chewing bark gums is added to improve to chewing oral health gums by reducingto improve salivary oral healthStreptococcus by reducing mutans salivarylevels [ 9St].reptococcus Honokiol (2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol)mutans levels [9]. Honokiol (2-(4-hydroxy-3-prop-2-enyl- phenyl)and magnolol-4-prop (4-Allyl-2-(5-allyl-2-hydroxy-phenyl)phenol)-2-enyl-phenol) and magnolol (4-Allyl-2-(5-allyl (Figure-2-hydroxy1) are the-phenyl)phenol) major active polyphenol (Figure 1) areconstituents the major presentactive polyphenol in M. officinalis constituentsbark [10 present]. Both in constituents M. officinalis have bark been[10]. shownBoth constituents to exert various have beencommon shown pharmacological to exert various effects, common including pharmacological anti-inflammatory, effects, antioxidative, including anti antidepressant-like,-inflammatory, antioxidative,and neuroprotective antidepressant activities-like, [11– and16]. Itneuroprotective has been reported activities that humans [11–16]. could It has be been regularly reported exposed that humansto the two could phytochemicals be regularly exposed in their daily to the lives, two throughphytochemicals either the in neutraceuticalstheir daily lives, or through the chewing either gum the neutraceuticalssources mentioned or the above chewing [17]. gum sources mentioned above [17]. (A) (B) FFigureigure 1 1.. ChemicalChemical structures structures of of honokiol honokiol (A (A) )and and magnolol magnolol ( (BB).). Honokiol strongly inhibits CYP1A2 activity with half maximal inhibitory concentration (IC50) Honokiol strongly inhibits CYP1A2 activity with half maximal inhibitory concentration (IC ) values of 2.1‒4.7 μM, while it moderately or strongly inhibits CYP2B6, 2C8, 2C9, and 2C19 activity50 values of 2.1–4.7 µM, while it moderately or strongly inhibits CYP2B6, 2C8, 2C9, and 2C19 activity with IC50 values of 3.9‒40.8 μM in human liver microsomes in vitro [18,19]. Magnolol also exerts with IC50 values of 3.9–40.8 µM in human liver microsomes in vitro [18,19]. Magnolol also exerts potent inhibitory effects on CYP1A2, 2B6, and 2C9 activity with C50 values of 5.4‒44.9 μM in human potent inhibitory effects on CYP1A2, 2B6, and 2C9 activity with C50 values of 5.4–44.9 µM in human liver microsomes as well as CYP1A, 2C, and 3A activity with IC50 values of 1.62‒35.0 μM in rat liver liver microsomes as well as CYP1A, 2C, and 3A activity with IC values of 1.62–35.0 µM in rat microsomes (RLM) in vitro [17,19]. Honokiol and magnolol could therefore50 potentially alter the in liver microsomes (RLM) in vitro [17,19]. Honokiol and magnolol could therefore potentially alter the vivo pharmacokinetics of drugs that are the substrates of CYP1A and 2C isoforms. However, limited in vivo pharmacokinetics of drugs that are the substrates of CYP1A and 2C isoforms. However, limited information is currently available regarding this issue, thereby warranting further investigation to improveinformation our understanding is currently available of drug regarding interactions this with issue, honokiol, thereby magnolol, warranting and further M. officinalis investigation. to improve our understanding of drug interactions with honokiol, magnolol, and M. officinalis. In the present study, the direct effect of honokiol and magnolol on hepatic CYP1A and 2C- mediatedIn the metabolism present study,was investigated the direct in effect vitro of using honokiol Sprague and-Dawley magnolol (SD) onRLM hepatic and in CYP1A vivo using and the2C-mediated SD rat model. metabolism The inhibitory was investigated potentialin of vitro honokiolusing and Sprague-Dawley magnolol on (SD)CYP RLM activity and inin RLM vivo usingwas the SD rat model. The inhibitory potential of honokiol and magnolol on CYP activity in RLM was assessed to establish its IC50. The in vivo pharmacokinetics of phenacetin and diclofenac, respective probeassessed substrates to establish
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