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Research Article Effects of Digeda-4 Decoction on the CYP450 Activities in Rats Using a Cocktail Method by HPLC

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Research Article Effects of Digeda-4 Decoction on the CYP450 Activities in Rats Using a Cocktail Method by HPLC Hindawi BioMed Research International Volume 2018, Article ID 1415082, 9 pages https://doi.org/10.1155/2018/1415082 Research Article Effects of Digeda-4 Decoction on the CYP450 Activities in Rats Using a Cocktail Method by HPLC Dong Zhang,1 Guo-dong Wu,1 Yan-dong Zhang,1 Jian-ping Xu,1 Hai-tao Zhen,1 and Min-hui Li 1,2 1 Baotou Medical College, Baotou 014060, China 2Inner Mongolia Institute of Traditional Chinese Medicine, Hohhot 010020, China Correspondence should be addressed to Min-hui Li; prof [email protected] Received 18 July 2018; Accepted 3 October 2018; Published 23 October 2018 Academic Editor: Jane Hanrahan Copyright © 2018 Dong Zhang et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Digeda-4 decoction is a traditional Mongolian medicine; its efects on cytochrome (CYP) enzymes are still unclear. CYP450 isoenzymes are the main drug metabolic enzymes, and their activities may be induced or inhibited by certain drugs, which lead to drug interactions in clinical use. Efects of Digeda-4 decoctionontheactivitiesofCYP450subtypeenzymesCYP1A2,CYP2C9, CYP2E1, CYP2C19, and CYP3A4 in rats were studied by cocktail method, and the pharmacokinetic parameters of fve specifc probe drugs (theophylline, tolbutamide, chlorzoxazone, omeprazole, and midazolam) were calculated by DAS sofware; changes of parameters can be used to evaluate the efects of Digeda-4 decoction on enzyme activities. Te experimental rats were divided into three groups: control group, Digeda group, and positive group. Rats in Digeda group were given Digeda-4 decoction through continuous gavage for 14 days. Afer fasting for 12 hours, the mixed probes drug solution was injected into the tail vein; the blood samples were collected through the orbital vein at diferent time points. Te concentrations of probe drugs in rat plasma were measured by HPLC. Compared with the control group, the half-life time (t1/2) of the pharmacokinetic parameters of theophylline, tolbutamide, omeprazole, and midazolam was prolonged, the area under the curve (AUC) increased, and the plasma clearance (CL) decreased in the Digeda group. Continuous gavage administration for 14 days may inhibit the activities of CYP450 subtype enzymes CYP1A2, CYP2C9, CYP2C19, and CYP3A4 of rats. Herb-drug interaction should be noted between Digeda-4 decoction and the drugs metabolized by CYP1A2, CYP2C9, CYP2C19, and CYP3A4. 1. Introduction ng/(mL x mg) afer combination with H. perforatum;the herb-drug interaction was the cause of organ rejection [2]. Traditional herbs are widely used throughout the world, H. perforatum also caused breakthrough bleeding in women while the herb-drug interactions resulting from which are who take steroids-containing contraceptive pills [3]. Ginseng increasingly reported. For example, Hypericum perforatum is is found in Eastern Asia and North America. Te roots and an inducer of cytochrome (CYP) 3A4 and can also inhibit or leaves of Ginseng can be used to make pills, cofee drinks, induce other subtype enzymes. H. perforatum could reduce energy drinks, and tea. A patient who took imatinib for blood levels of indinavir, warfarin, digoxin, amitriptyline, 7 years sufered liver damage afer taking Ginseng as an midazolam, cyclosporine, and so forth [1]. Tere are sev- energy drink for 3 months, which may have been caused eral cases reporting that H. perforatum reduced the blood by interaction between imatinib and Ginseng [4]. Tis inter- concentration of cyclosporine, resulting in organ rejection, action may be due to the active constituents in Ginseng, such as the case of a kidney transplant patient who had been which infuenced the expression of the CYP450 enzymes taking cyclosporin for several years in whom organ rejection [5]. Numerous studies indicate that herbal medicines can appeared afer taking H. perforatum. Afer the challenge afect the metabolism of drugs’ combined use with them by test, the same result was obtained. Te blood concentration inducing or inhibiting drug-metabolizing enzymes, which of cyclosporin decreased to 0.48 ng/(mL x mg) from 0.84 pose a great risk. Terefore, it is urgent to study the efects 2 BioMed Research International of herbs on CYP450 enzymes and to guide the clinical interactions (DDIs) [23, 24]. Enzyme inhibition by inhibitor application of herbs in a better way. drugs could lead to concentration increase of another drug “Digeda-4 decoction” (alias of Leizhuhua-4 decoction) in plasma and increase the risk of adverse drug reactions is a traditional Mongolian medicine, which is composed of (ADRs) or exert toxic efects [25]. It is important to study Lomatognii Herba (Lomatogonium rotatum Fries ex Nym.), the induction or inhibition of CYP450 enzyme activity in Picrorrhizae Rhizoma (Picrorhiza scrophulariifora Pennell), order to predict the potential DDIs, thereby to avoid the Gardeniae Fructus (Gardenia jasminoides Ellis), and Dianthi occurrence of adverse reactions. Te cocktail approach has Herba (Dianthus superbus L.); the proportion of the four become one of the basic analytical tools to evaluate DDIs herbs is 1:1:1:1. It cames from Zhen Zhi Ming Yi Dian and in vivo. Compounds specifcally catalyzed by each CYP is included in the pharmaceutical standards of the ministry isoform, known as probe drugs, have been widely used of health of the People's Republic of China and Mongolian to assess the activity of various CYP450s in this approach Drug Standards Booklet 1998 [6]. Lomatogonium rotatum is [26]. cultivated mainly in East-Central Inner Mongolia, including To evaluate the safety of clinical combination use, the Hexigten banner, Duolun county, Zhenglan banner, and so infuences of Digeda-4 decoction on the activities of fve forth [7]. Tis plant mainly contains compounds such as CYP450enzymesinratsareevaluatedaccordingtothephar- favonoids, triterpenoids, iridoids, and cleaved iridoids [8]. macokinetic parameters’ changes using fve specifc probe Picrorhiza scrophulariifora is mainly distributed in northwest drugs (theophylline for CYP1A2, tolbutamide for CYP2C9, of Yunnan province and the alpine meadows and stone chlorzoxazone for CYP2E1, omeprazole for CYP2C19, and heaps of Tibet [9]. Te plant contains a large amount of midazolam for CYP3A4). Two sensitive and specifc HPLC iridoid glycosides, phenylethanoid glycosides, phenol glyco- methods were used to quantify the concentration of fve sides, cucurbitane triterpenoids, and a very small amount of probe drugs. favonoids and aromatic acids [10]. Te authentic production areas of Gardenia jasminoides are Jiangxi, Qingjiang, Fujian, 2. Materials and Methods and Hubei [11]. Its chemical compositions include iridoids, iridoid glucosides, triterpenoids, organic acids, and volatile 2.1. Chemicals and Reagents. Digeda-4 decoction was compounds, among which geniposide, genipin, gardeno- purchased from the pharmacy department of Mongolian side, and crocin are the major bioactive compounds [12]. traditional Chinese hospital (Baotou, Inner Mongolia, Dianthus superbus is distributed throughout Inner Mongolia, China).Teophylline,tolbutamide,chlorzoxazone,mida- Liaoning, Hebei, Henan, Hubei, Jiangsu, and Zhejiang; the zolam, omeprazole, (all > 98%), and the internal standard (IS) main cultivated areas are the east and southeast of Daxing tinidazole were purchased from Dalian Meilun Biotech Co., anling forest region [13, 14]. It contains triterpenoid saponins, Ltd. (Dalian, China). HPLC-grade acetonitrile and methanol favones, cyclopeptides, frangulic acid, and polysaccharide were from Merck Company (Darmstadt, Germany). All [14–16]. Some scholars have studied that Digeda-4 decoction other chemicals were of analytical grade. Ultrapure water contains more swertiamarin and also contains geniposide, (resistance > 18 mΩ) was prepared using a Millipore Milli-Q picrosides II, and total favonoids of Dianthus superbus [17]. purifcation system (Bedford, USA). Tis decoction is benefcial to liver and cholecyst, ofen combined with other Chinese and Mongolian prescriptions 2.2. Animals. Wistar rats (male, 220 ± 20 g) were pur- or western medicines in clinical application [18]. Modern chased from Beijing Sibefu Biotechnology Co., Ltd. Ani- pharmacological studies have shown that Digeda-4 decoction mals were housed under natural light-dark cycle conditions ∘ has a protective efect on chemical liver injury and has a with controlled temperature (22 C). All rats were housed regulatory efect on the lipid metabolism disorder of rats at Laboratory Animal Research Center of Baotou Medical caused by carbon tetrachloride [19, 20]. However, whether College. All experimental procedures were approved ethically Digeda-4 decoction can afect the metabolic process of its by the Administration Committee of Experimental Animals coadministered drugs by infuencing metabolic enzymes is of Baotou Medical College. still unknown. CYP450 is a family of heme proteins that are involved 2.3. Instrumentation and Conditions. UltiMate3000 HPLC in the metabolism of endogenous and exogenous substances equipped with diode array detector was used to analyze [21]. Tis study involved fve important CYP isozymes, the compounds. Teophylline, tolbutamide, chlorzoxazone, CYP1A2,CYP2C9,CYP2E1,CYP2C19,andCYP3A4.Tese omeprazole, midazolam, and tinidazole (IS) were separated enzymes were chosen because they account for a high using Eclipse XDB-C18 (4.6 × 150 mm, 5 �m, Agilent, USA) ∘ proportion of total CYPs (CYP3A
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