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Effects of Paeonia emodi on hepatic cytochrome P450 (CYP3A2 and CYP2C11) expression and pharmacokinetics of carbamazepine in rats
Biomedicine & Pharmacotherapy 90 (2017) 694–698
Available online at
ScienceDirect www.sciencedirect.com
Effects of Paeonia emodi on hepatic cytochrome P450 (CYP3A2 and CYP2C11) expression and pharmacokinetics of carbamazepine in rats Mohammad Raisha,* , Ajaz Ahmadb , Khalid M. Alkharfyb,* , Basit L. Janb , Kazi Mohsina , Abdul Ahada , Fahad I. Al-Jenoobia , Abdullah M. Al-Mohizeaa a b
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
A R T I C L E I N F O
Article history: Received 1 March 2017 Received in revised form 30 March 2017 Accepted 10 April 2017 Key Points: Paeonia emodi Cytochrome P450 Carbamazepine Pharmacokinetics
A B S T R A C T
Herbal medicines, dietary supplements, and other foods may pharmacokinetically and/or pharmacodynamically interact with carbamazepine (CBZ), which could lead to potential clinical consequences. Paeonia emodi (PE) is one of the herbs used as complementary therapy in the treatment of epileptic patients in some cultures, and may also be co-administered with CBZ. This study evaluates the effects of PE on the pharmacokinetics of CBZ and determines a possible mechanism of interaction. Rats were administered vehicle saline or PE (200 mg/kg, p.o. daily for 7 days), then administered a single CBZ dose (80 mg/kg, p.o.) on day 7. Plasma samples were analyzed for CBZ concentrations using a sensitive reversed-phase high-performance liquid chromatography (RP-HPLC) assay. Pharmacokinetic parameters were calculated using non-compartmental analysis. The co-administration of PE with CBZ resulted in increased plasma maximum concentration (Cmax), area under the curve (AUC0-1), and half-life (T1/2), by 14.61%, 48.12%, and 43.72%, respectively. The calculated oral clearance (CL/F) was reduced by 33.54%, while the volume of distribution (Vss) was unaffected. The PE extract also showed a significant potential to reduce CYP3A and CYP2C protein expression by approximately 50%. Therefore, a reduction in the metabolic capacity responsible for CBZ clearance appears to be the mechanism behind this herb-drug interaction. Consequently, the concomitant administration of PE and CBZ should be viewed cautiously. Further studies are needed to determine the clinical relevance of these observations. © 2017 Elsevier Masson SAS. All rights reserved.
1. Introduction Epilepsy is a prevalent chronic neurological disorder characterized by episodes of seizure. Carbamazepine (CBZ), introduced in the 1960s, remains one of the most frequently prescribed antiepileptic drugs worldwide and has established efficacy for the treatment of partial seizures, generalized tonic-clonic seizures, trigeminal neuralgia, and bipolar disorders [1–6]. Despite its widespread clinical use, CBZ possesses several pharmacokinetic properties which make it prone to interaction with co-administered substances, including drugs, herbal products, and other foods [7]. Paeonia emodi (PE) is an herbaceous plant that has been widely explored in traditional and indigenous systems of Unani medicine.
* Corresponding authors at: Department of Clinical Pharmacy/Pharmaceutics, College of Pharmacy, King Saud University, PO Box 2457, Riyadh, 11451, Saudi Arabia. E-mail addresses: [email protected] (M. Raish), [email protected] (K.M. Alkharfy). http://dx.doi.org/10.1016/j.biopha.2017.04.015 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.
This plant has been used to treat epileptic disorders [8]. The roots and rhizomes are used to treat different disorders such as uterine diseases, epileptic disorders, nervine tonic, and as blood purifier, while the seeds have purgative properties [7,8]. PE constituents include triterpenes, monoterpene phenolics, glycosides, and anthraquinone. The biological activities that have been reported for these phytoconstituents include anticoagulant and cardioprotective, inhibition of b-glucuronidase and antioxidant activity, and relaxation of airway obstruction [8–10]. Herbal medicines, dietary supplements, and other foods may interact with CBZ pharmacokinetically and/or pharmacodynamically, leading to potential clinical concerns. The use of phytomedicines has become increasingly popular; therefore, the incidence of patients taking CBZ with herbal and dietary supplements is high, and it is necessary to report the safety issues of such concurrent use [11,12]. There are no reports hitherto about the pharmacokinetic interactions between CBZ and PE. Since PE is one of the herbs used as an adjuvant therapy by some epileptic patients, it may be administered concomitantly with CBZ in clinical situations. Therefore, the present study was conducted to investigate the
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effects of PE on the pharmacokinetics of CBZ and to determine the possible mechanism of interaction between PE and CBZ. 2. Experimental 2.1. Drugs, chemicals, and plant materials CBZ (C4024) and omeprazole (IS, O104) were purchased from Sigma-Aldrich (St Louis, MO, USA). Acetonitrile (361881) and methanol (261091) (HPLC grade) were obtained from Panreac Chemicals (Barcelona, Spain), while potassium dihydrogen phosphate (P34783/151) was procured from Winlab Ltd. (Maidenhead, Berkshire, UK). Milli-Q water was produced in our laboratory by a purification system (Millipore Corp., Billerica, MA, USA). AntiCYP3A2 (LS-C36108) and CYP2C11 (LS-C64214) antibodies were purchased from LifeSpan Biosciences, Inc. (Seattle, WA, USA). All chemical reagents used were of analytical grade. PE roots were purchased from a local market in Riyadh, Saudi Arabia, and were authenticated by an herbarium. Extraction of the roots was conducted according to previously reported methods [8,13,14]. Briefly, the powdered roots of PE were extracted using a Soxhlet apparatus (80 C) with 90% ethyl alcohol under boiling temperatures for 6 h, and then filtered through a mesh cloth to collect the extract. The extract was then concentrated under reduced pressure at 45 C to obtain the crude extract. 2.2. Animals Healthy male Wistar rats (180–200 g) were obtained from the Central Animal House Facility of the College of Pharmacy, King Saud University (Riyadh, Saudi Arabia), and were divided into two groups (n = 6) and placed in plastic animal cages with a 12-h light/ dark cycle (25 2 C) in accordance with the animal facilities guidelines (Clearance No. 396; March 21, 2014). The rats were provided water ad libitum and fed standard rat chow diet. The animals were acclimatized to laboratory conditions for a week prior to experiments. 2.3. Pharmacokinetic studies The animals were divided into two groups (n = 6 each), and fasted for 12 h before the experiment, while water was allowed ad libitum. Group I rats were treated with normal saline orally for 6 days and received CBZ (80 mg/kg p.o.) on day 7. Group II rats were treated with an oral dose of PE extract (200 mg/kg) for 7 consecutive days and received CBZ (80 mg/kg p.o.) on day 7, one hour after PE administration; normal controls were run in parallel. Blood samples were collected from retro-orbital plexus in tubes containing di-sodium EDTA at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 h after CBZ administration. Plasma was separated by centrifugation at 2500 g for 10 min and transferred to pre-labeled Eppendorf tubes for subsequent simultaneous analysis of CBZ by RP-HPLC. At the end of the experiments, the rats were anesthetized under light ether and euthanized, and liver tissue samples were excised for western blotting.
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filtered through a 0.45 mm Millipore filter and degassed prior to use. The flow rate of the mobile phase was set at 0.8 ml/min. CBZ was analyzed at a wavelength of 285 nm. The chromatographic identification and quantification was carried out at room temperature (25 1 C). A Symmetry1 C18 (5 mm, 3.9 150 mm) column was used to elute the compounds of interest at a lmax = 254 nm. Signal output was carried out by using Lab Solutions 32 software, version 3.05 (Shimadzu, Tokyo, Japan). The analysis of the non-compartmental pharmacokinetic parameters was performed using PK Solver software (version 1.0). The calculated parameters were: area under plasma concentration-time curve (AUC) using the linear trapezoid method; area under the first moment curve (AUMC); mean residence time (MRT), where MRT = AUMC/AUC; volume of distribution (Vz), where Vz = (dose/AUC x lz); total clearance (CL), where CL = dose/AUC, and absorption rate constant (Ka), where Ka = (1/MAT). The terminal elimination rate constant (lz) was calculated from the slope of the logarithm of the plasma concentration versus time. The apparent elimination half-life (T1/2) was calculated as ln2/lz. The maximum plasma concentration (Cmax) and time to maximum concentration (Tmax) were determined empirically directly from the time-concentration curve. 2.5. CYP3A2 and CYP2C11 hepatic protein expression in rats Western blot analysis were performed according to Towbin et al. [16] with minor modification to quantify the effect of PE on hepatic expression of CYP3A2, CYP2C11, and b-actin. Hepatic protein (25 mg) was denatured by diluting with loading buffer and boiling for 5 min at 100 C. Each sample was loaded onto a 10% SDSpolyacrylamide gel and subjected to electrophoresis at 100 V for 2 h. Separated proteins were transferred to trans-Blot PVDF membrane (0.45 mm) in a buffer containing 25 mM Tri–HCl, 192 m glycine, and 20% methanol (v/v). The blots were blocked overnight at 4 C in a solution containing 5% skim milk powder, 2% bovine serum albumin, and 0.5% Tween-20 in Tris-buffered saline (TBS) buffer. The blots were rinsed three times in wash buffer (0.1% Tween-20 in TBS). Membranes were incubated with primary antibodies against CYP3A2 (1/800, LS-C36108), CYP2C11 (1/1000, LS-C64214) and b-actin (1/1000, sc-47778) for 2 h at 4 C in TBS containing 0.01% sodium azide and 0.05% Tween-20. Blots were rinsed three times with wash buffer, followed by incubation with horseradish peroxidase-conjugated anti-rabbit or anti-mouse IgG secondary antibodies (1/5000 dilution) for 1 h at room temperature and washed. Bands were visualized using LuminataTM Western Chemiluminescent HRP Substrates (Millipore, Billerica, MA, USA) and a densitometric analysis of the immunoblots was performed using LI-COR C-DiGit Blot Scanners (Lincoln, NE, USA). 2.6. Statistical analysis The data are expressed as mean standard error of mean (SEM). The significance was determined by applying Students ttest or one-way analysis of variance as appropriate; p values of < 0.05 were considered significant.
2.4. Bioassay and pharmacokinetic analysis 3. Results CBZ plasma concentrations were measured using a validated high-performance liquid chromatographic analytical method previously reported by our laboratory [15]. Briefly, the HPLC (Shimadzu, Kyoto, Japan) system consisted of a SIL 20A with auto sampler, model LC 20AD dual piston solvent delivery pump, model SPD 20A dual UV detector, and vacuum degasser. The mobile phase ratio containing methanol: acetonitrile: potassium dihydrogen phosphate buffer (20 mM) in the ratio of 65:2:33 v/v/v that was
3.1. Effect of PE on CBZ pharmacokinetics The HPLC chromatograms of both PE extract and CBZ are shown in Fig. 1. The estimated pharmacokinetic parameters of CBZ alone and co-administered with PE are listed in Table 1 and Fig. 2. The Cmax of oral administration of CBZ in rats was found to be 4.82 0.20 mg/ml with a Tmax at 2 h; in animals co-administered
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Fig. 1. HPLC chromatogram of plasma sample from a rat administered with both PE (200 mg/kg p.o. for seven days) extract and Carbamazepine (80 mg/kg p.o.).
PE, Cmax of CBZ was 5.52 0.93 mg/ml with a Tmax of approximately 2 h. The co-administration of PE with CBZ showed increases in AUC0–1 by approximately 40%, T1/2 by 44%, and MRT by 33% as compared to CBZ alone (p < 0.05). Conversely, the calculated Kel, CL/F, and Vz decreased by 31%, 33% and 3%, respectively. This decrease in CL/F resulted in a significant increase in CBZ residence time by approximately 33% after a single administration compared to rats that did not receive PE (p < 0.05). 3.2. Effect of PE on CYP3A2 and CYP2C11 hepatic protein expression in rats Hepatic expression of CYP3A2 and CYP2C11 proteins were markedly decreased following PE treatment as compared with b-actin controls (Fig. 3). CBZ treatment caused a significant increase in CYP3A2 and CYP2C11 protein levels compared to normal controls by 3.2 and 2.7-fold, respectively (p < 0.05). In rats treated with PE, there was an approximate 50% inhibition of CBZinduced CYP3A2 and CYP2C11 expression (p < 0.05). 4. Discussion Concomitant use of herbal medicine may mimic, augment, or reduce the activity of drugs [17]. Antiepileptic therapy is usually prolonged and requires monitoring of drug concentration to reduce the risk of side effects [18]. CBZ is a narrow-spectrum antiepileptic drug and is subject to potential herb-drug or fooddrug interactions [19]. Patients are often uninformed of possible herb-drug interactions, and many do not consider herbal medicines as drugs. Consequently, they do not inform their
healthcare providers about a concomitant use of herbal products [20]. PE roots have been used to treat epilepsy over many centuries [10]. The prevalent chemical moieties in PE are monoterpene glycosides, triterpenes, anthraquinone, phenolics, and oligo stilbenes [10]. Taking into account the high prevalence of PE use for epilepsy in the subcontinent, the risk of the co-administration of PE with narrow-therapeutic antiepileptics such as CBZ cannot be underestimated. To the best of our knowledge, this is the first report that explores the effect of PE on the pharmacokinetics of CBZ after oral administration using an animal model. The commonly used oral dose of PE is about 6 g per day; therefore, we calculated an equivalent rat dose [21]. CBZ is an important substrate for CYP3A4 and CYP2C9 in humans, and CYP3A2 and CYP2C11 in rats [22,23]. The overall rate of biotransformation of CBZ in rats is distinctly different from that in humans; the metabolic clearance is more than 10-fold faster in rats [24,25]. Therefore, the current study employed 24-h experiments in rats. Prior treatment with PE for seven days caused an escalation in the Cmax, AUC0-1, and T1/2 of CBZ, and a reduction in its clearance. This indicates a decline in CBZ metabolism following the co-administration of PE in rats. CBZ is largely metabolized in the liver with only 5% of the drug eliminate unchanged [26]. The primary path of metabolism is conversion to an active metabolite CBZ 10.11-epoxide (CBZ-E), which has the same efficacy as the parent compound [22]. This reaction in humans is mainly catalyzed by CYP3A4, although CYP2C8 also plays a role, and participation of CYP3A5 has also been proposed [27,28]. Drugs that inhibit the metabolism of CBZ frequently lead to augmentation of plasma levels and signs of toxicity. Grapefruit, kinnow,
Table 1 Non-compartmental pharmacokinetic parameters of CBZ and CBZ with PE following oral administration in rats. Parameter
CBZ
CBZ + PE
% Change
p-value
lz (1/h)
0.15 0.01 4.76 0.31 2.00 0.00 4.82 0.20 35.20 1.97 36.77 2.37 278.60 32.51 7.47 0.41 14.95 0.26 2.21 0.15
0.10 0.004 6.84 0.30 2.00 0.00 5.52 0.09 49.17 0.45 54.46 0.98 544.58 29.82 9.97 0.37 14.48 0.41 1.47 0.02
31.14 43.72 0.00 14.61 39.67 48.12 95.47 33.46 3.14 33.54
0.0012 0.0007 1.00 0.0065 0.0001 0.0001 0.0002 0.001 0.1823 0.0005
T1/2 (h) Tmax (h) Cmax (mg/ml) AUC0-t (mg/ml*h) AUC0-1 (mg/ml*h) AUMC0-1 (mg/ml*h2) MRT0-1 (h) Vz/F ((mg/kg)/(mg/ml)) CL/F ((mg/kg)/(mg/ml)/h)
Fig. 2. A representative plasma concentration-time curve of CBZ (80 mg/kg p.o.) administered with/without PE (200 mg/kg p.o. for seven days) in rats.
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Fig. 3. Expression of hepatic CYP3A2 and CYP2C11 protein expression in rats following CBZ administration with and without PE treatment. All values represent mean SEM. *p < 0.05 (Control); #p < 0.05 (CBZ); ANOVA, followed by Dunnett's multiple comparison test.
pomegranate, and star fruit juice have the ability to increase Cmax and AUC of CBZ due to inhibition of CYP3A4 [25,29–31]. The Chinese herbs Hu-gan-ning pian, ginkgo biloba, Xiao-yao-san, and Jia-wei-xiao-yao-san decreased the plasma level and oral bioavailability of CBZ by enhancing the rate of metabolism of CBZ through CYP3A4 induction [32,33]. Drugs that inhibit metabolism of CBZ frequently lead to accumulation of CBZ and signs of toxicity, whereas drugs that enhance the metabolism of CBZ can lead to no effect or sub-therapeutic effect. Moreover, the principle metabolite of CBZ, CBZ-10,11 epoxide, is pharmacologically active and may contribute to the toxicities of CBZ [34]. Some PE constituents, including monoterpene glycosides, triterpenes, anthraquinone, phenolics and oligo stilbenes, are known to be potent inhibitors of CYP3A and CYP2C9 [35,36]. These compounds function as competitive substrates for cytochrome P450 and therefore block the metabolism of CBZ. A detailed biochemical mechanism has been established with a comprehensive kinetic study [37–39]. In order to elucidate the possible mechanism, we performed western blot analysis, which clearly demonstrated a significant inhibition of CYP3A2 and CYP2C11 hepatic protein expression in PE-treated rats. It is an established fact that CBZ itself induces CYP3A and CYP2C protein expression [22,40]. The current study has shown that PE interferes with CBZ pharmacokinetics by increasing Cmax, AUC0-1 and T1/2, and a reducing its clearance. These results are in agreement with several pharmacokinetic studies where the bioavailability of CBZ is enhanced due to interactions with CYP3A inhibitors [25,41]. The mechanism might also involve the site of CBZ absorption in the intestine. Thus, increased oral absorption of CBZ with PE co-administration in rats could be the result , at least partially, of a modulation of P-glycoprotein activity. However, it is still under debate whether CBZ is a substrate for Pglycoprotein [36,42].
5. Conclusion The present study demonstrated that PE extract has the potential to alter the pharmacokinetics of CBZ by a significant reduction in protein expression of CYP3A2 and CYP2C11 (50% and
55.55%, respectively). This was associated with a substantial reduction in CBZ clearance and an increase in its AUC and T1/2. Therefore, the co-administration of PE with CBZ should be viewed cautiously. Further studies in humans are needed to determine the clinical relevance of such observations. Conflict of interest The authors declare that they have no conflicts of interest. Acknowledgment The author would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding through research group number (RG# 1435-017). References [1] N.F. Moran, K. Poole, G. Bell, J. Solomon, S. Kendall, M. McCarthy, D. McCormick, L. Nashef, J. Sander, S.D. Shorvon, Epilepsy in the United Kingdom: seizure frequency and severity, anti-epileptic drug utilization and impact on life in 1652 people with epilepsy, Seizure 13 (6) (2004) 425–433. [2] L.P. Hsieh, C.Y. Huang, Antiepileptic drug utilization in Taiwan: analysis of prescription using National Health Insurance database, Epilepsy Res. 84 (1) (2009) 21–27. [3] I. Bielen, A. Sruk, M. Planjar-Prvan, L. Cvitanovic-Sojat, M. Kosicek, B. BergmanMarkovic, R. Baraba, S. Butkovic-Soldo, Age-related pattern of the antiepileptic drug utilization in active epilepsy: a population-based survey, Coll. Antropol. 33 (2) (2009) 659–663. [4] Z. Tolou-Ghamari, M. Zare, J.M. Habibabadi, M.R. Najafi, A quick review of carbamazepine pharmacokinetics in epilepsy from 1953 to 2012, J. Res. Med. Sci. 18 (Suppl. (1)) (2013) S81–5. [5] T. Okuma, A. Kishimoto, A history of investigation on the mood stabilizing effect of carbamazepine in Japan, Psychiatry Clin. Neurosci. 52 (1) (1998) 3–12. [6] A.L. Grzesiak, M. Lang, K. Kim, A.J. Matzger, Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I, J. Pharm. Sci. 92 (11) (2003) 2260–2271. [7] T.A. Ketter, R.M. Post, K. Worthington, Principles of clinically important drug interactions with carbamazepine. Part I, J. Clin. Psychopharmacol. 11 (3) (1991) 198–203. [8] AZSM, S.S. Shadab Ahmad Pathan, F.J. Ahmad, S.S. Jamil, R.K. Khar, Effect of repeated administration of paeonia emodi wall root extract in experimental models of epilepsy and behavior, J. Pharmacol. Toxicol. 7 (2012) 64–74. [9] A. Ahmad, K.M. Alkharfy, T.A. Wani, M. Raish, Application of Box-Behnken design for ultrasonic-assisted extraction of polysaccharides from Paeonia emodi, Int. J. Biol. Macromol. 72 (2015) 990–997.
698
M. Raish et al. / Biomedicine & Pharmacotherapy 90 (2017) 694–698
[10] B.A. Zargar, M.H. Masoodi, B.A. Khan, S. Akbar, Paeonia emodi Royle: ethnomedicinal uses, phytochemistry and pharmacology, Phytochem. Lett. 6 (2) (2013) 261–266. [11] L.C. Chen, Y.F. Chen, L.L. Yang, M.H. Chou, M.F. Lin, Drug utilization pattern of antiepileptic drugs and traditional Chinese medicines in a general hospital in Taiwan—a pharmaco-epidemiologic study, J. Clin. Pharm. Ther. 25 (2) (2000) 125–129. [12] K. Liow, E. Ablah, J.C. Nguyen, T. Sadler, D. Wolfe, K.D. Tran, L. Guo, T. Hoang, Pattern and frequency of use of complementary and alternative medicine among patients with epilepsy in the midwestern United States, Epilepsy Behav. 10 (4) (2007) 576–582. [13] M.A. Taous Khan, Hamayun Khan, Mir Azam Khan, Biological activities of aerial parts of Paeonia emodi Wall, Afr. J. Biotechnol. 4 (11) (2005) 1313–1316. [14] T. Khan, M. Ahmad, M. Nisar, M.A. Lodhi, M.I. Choudhary, Enzyme inhibition and radical scavenging activities of aerial parts of Paeonia emodi Wall (Paeoniaceae), J. Enzyme Inhib. Med. Chem. 20 (3) (2005) 245–249. [15] F.I.A.-J. Khalid M. Alkharfy, Mohd. Aftab Alam, Abdullah M. Al-Mohizea,, H.M.K. Saleh A. Al-Suwayeh, RaoM. A. Khan and Iqbal Muzaffar, Lepidium Sativum but not Nigella Sativa Affects Carbamazepine Disposition in an Animal Model, Drug Metabolism Letters, 2013, 7, 47–51 7 (2013) 47–51. [16] H. Towbin, T. Staehelin, J. Gordon, Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications, Proc. Natl. Acad. Sci. U. S. A. 76 (9) (1979) 4350–4354. [17] A. Fugh-Berman, E. Ernst, Herb-drug interactions: review and assessment of report reliability, Br. J. Clin. Pharmacol. 52 (5) (2001) 587–595. [18] S.Y. Fong, Q. Gao, Z. Zuo, Interaction of carbamazepine with herbs, dietary supplements, and food: a systematic review, Evid. Based Complement. Alternat. Med. 2013 (2013) 898261. [19] T.a. Ketter, R.m. post, K. worthington, Principles of clinically important drug interactions with carbamazepine. Part I, J. Clin. Psychopharmacol. 11 (3) (1991) 198–202. [20] C. Tarirai, A.M. Viljoen, J.H. Hamman, Herb-drug pharmacokinetic interactions reviewed, Expert Opin. Drug Metab. Toxicol. 6 (12) (2010) 1515–1538. [21] S. Reagan-Shaw, M. Nihal, N. Ahmad, Dose translation from animal to human studies revisited, FASEB J. 22 (3) (2008) 659–661. [22] R.E. Pearce, W. Lu, Y. Wang, J.P. Uetrecht, M.A. Correia, J.S. Leeder, Pathways of carbamazepine bioactivation in vitro. III. The role of human cytochrome P450 enzymes in the formation of 2,3-dihydroxycarbamazepine, Drug Metab. Dispos. 36 (8) (2008) 1637–1649. [23] T. Tateishi, M. Asoh, H. Nakura, M. Watanabe, M. Tanaka, T. Kumai, S. Kobayashi, Carbamazepine induces multiple cytochrome P450 subfamilies in rats, Chem. Biol. Interact. 117 (3) (1999) 257–268. [24] J. Faigle, Carbamazepine: chemistry and biotransformation, Antiepileptic Drugs (1995) 499–513. [25] M. Hidaka, M. Okumura, K. Fujita, T. Ogikubo, K. Yamasaki, T. Iwakiri, N. Setoguchi, K. Arimori, Effects of pomegranate juice on human cytochrome p450 3A (CYP3A) and carbamazepine pharmacokinetics in rats, Drug Metab. Dispos. 33 (5) (2005) 644–648. [26] K.A. Kim, S.O. Oh, P.W. Park, J.Y. Park, Effect of probenecid on the pharmacokinetics of carbamazepine in healthy subjects, Eur. J. Clin. Pharmacol. 61 (4) (2005) 275–280.
[27] S.I. Hung, W.H. Chung, Z.S. Liu, C.H. Chen, M.S. Hsih, R.C. Hui, C.Y. Chu, Y.T. Chen, Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese, Pharmacogenomics 11 (3) (2010) 349–356. [28] B.M. Kerr, K.E. Thummel, C.J. Wurden, S.M. Klein, D.L. Kroetz, F.J. Gonzalez, R.H. Levy, Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxide formation, Biochem. Pharmacol. 47 (11) (1994) 1969–1979. [29] S.K. Garg, V.K. Bhargava, H. James, N. Kumar, S. Prabhakar, Influence of kinnow juice on the bioavailability of carbamazepine in healthy male volunteers, Neurol. India 46 (3) (1998) 229–231. [30] S.K. Garg, N. Kumar, V.K. Bhargava, S.K. Prabhakar, Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy, Clin. Pharmacol. Ther. 64 (3) (1998) 286–288. [31] M. Hidaka, M. Okumura, T. Ogikubo, H. Kai, K.I. Fujita, T. Iwakiri, K. Yamasaki, N. Setoguchi, N. Matsunaga, K. Arimori, Transient inhibition of Cyp3A in rats by star fruit juice, Drug Metab. Dispos. 34 (3) (2006) 343–345. [32] Z.J. Zhang, W.H. Kang, Q. Li, Q.R. Tan, The beneficial effects of the herbal medicine free and easy Wanderer Plus (FEWP) for mood disorders: doubleblind, placebo-controlled studies, J. Psychiatr. Res. 41 (10) (2007) 828–836. [33] C.R. Harish, M. Rajkumar, C. Veeresham, Pharmacokinetic interaction of ginkgo biloba with carbamazepine, Planta Med. 75 (4) (2009) 454–454. [34] Y.C. Wong, S. Qian, Z. Zuo, Regioselective biotransformation of CNS drugs and its clinical impact on adverse drug reactions, Expert Opin. Drug Met. 8 (7) (2012) 833–854. [35] M. Miyazawa, M. Shindo, T. Shimada, Roles of cytochrome P450 3A enzymes in the 2-hydroxylation of 1 4-cineole, a monoterpene cyclic ether, by rat and human liver microsomes, Xenobiotica 31 (10) (2001) 713–723. [36] L. Basheer, Z. Kerem, Interactions between CYP3A4 and dietary polyphenols, Oxid. Med. Cell. Longevity 2015 (2015) 854015. [37] J. Ehlting, B. Hamberger, R. Million-Rousseau, D. Werck-Reichhart, Cytochromes P450 in phenolic metabolism, Phytochem. Rev. 5 (2–3) (2006) 239–270. [38] Y. Kapelyukh, M.J. Paine, J.-D. Maréchal, M.J. Sutcliffe, C.R. Wolf, G.C. Roberts, Multiple substrate binding by cytochrome P450 3A4: estimation of the number of bound substrate molecules, Drug Metab. Dispos. 36 (10) (2008) 2136–2144. [39] J. Zhao, J. Zhao, S. Franzen, The regulatory implications of hydroquinone for the multifunctional enzyme dehaloperoxidase-hemoglobin from Amphitrite ornata, J. Phys. Chem. B 117 (47) (2013) 14615–14624. [40] N. Ohnishi, Y. Yonekawa, S. Nakasako, K. Nagasawa, T. Yokoyama, M. Yoshioka, K. Kuroda, Studies on interactions between traditional herbal and Western medicines. I. Effects of Sho-seiryu-to on the pharmacokinetics of carbamazepine in rats, Biol. Pharm. Bull. 22 (5) (1999) 527–531. [41] S.K. Garg, N. Kumar, V.K. Bhargava, S.K. Prabhakar, Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy, Clin. Pharmacol. Ther. 64 (3) (1998) 286–288. [42] E.J. Wang, M. Barecki-Roach, W.W. Johnson, Elevation of P-glycoprotein function by a catechin in green tea, Biochem. Biophys. Res. Commun. 297 (2) (2002) 412–418.
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Effects of Paeonia emodi on hepatic cytochrome P450 (CYP3A2 and CYP2C11) expression and pharmacokinetics of carbamazepine in rats Mohammad Raisha,* , Ajaz Ahmadb , Khalid M. Alkharfyb,* , Basit L. Janb , Kazi Mohsina , Abdul Ahada , Fahad I. Al-Jenoobia , Abdullah M. Al-Mohizeaa a b
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
A R T I C L E I N F O
Article history: Received 1 March 2017 Received in revised form 30 March 2017 Accepted 10 April 2017 Key Points: Paeonia emodi Cytochrome P450 Carbamazepine Pharmacokinetics
A B S T R A C T
Herbal medicines, dietary supplements, and other foods may pharmacokinetically and/or pharmacodynamically interact with carbamazepine (CBZ), which could lead to potential clinical consequences. Paeonia emodi (PE) is one of the herbs used as complementary therapy in the treatment of epileptic patients in some cultures, and may also be co-administered with CBZ. This study evaluates the effects of PE on the pharmacokinetics of CBZ and determines a possible mechanism of interaction. Rats were administered vehicle saline or PE (200 mg/kg, p.o. daily for 7 days), then administered a single CBZ dose (80 mg/kg, p.o.) on day 7. Plasma samples were analyzed for CBZ concentrations using a sensitive reversed-phase high-performance liquid chromatography (RP-HPLC) assay. Pharmacokinetic parameters were calculated using non-compartmental analysis. The co-administration of PE with CBZ resulted in increased plasma maximum concentration (Cmax), area under the curve (AUC0-1), and half-life (T1/2), by 14.61%, 48.12%, and 43.72%, respectively. The calculated oral clearance (CL/F) was reduced by 33.54%, while the volume of distribution (Vss) was unaffected. The PE extract also showed a significant potential to reduce CYP3A and CYP2C protein expression by approximately 50%. Therefore, a reduction in the metabolic capacity responsible for CBZ clearance appears to be the mechanism behind this herb-drug interaction. Consequently, the concomitant administration of PE and CBZ should be viewed cautiously. Further studies are needed to determine the clinical relevance of these observations. © 2017 Elsevier Masson SAS. All rights reserved.
1. Introduction Epilepsy is a prevalent chronic neurological disorder characterized by episodes of seizure. Carbamazepine (CBZ), introduced in the 1960s, remains one of the most frequently prescribed antiepileptic drugs worldwide and has established efficacy for the treatment of partial seizures, generalized tonic-clonic seizures, trigeminal neuralgia, and bipolar disorders [1–6]. Despite its widespread clinical use, CBZ possesses several pharmacokinetic properties which make it prone to interaction with co-administered substances, including drugs, herbal products, and other foods [7]. Paeonia emodi (PE) is an herbaceous plant that has been widely explored in traditional and indigenous systems of Unani medicine.
* Corresponding authors at: Department of Clinical Pharmacy/Pharmaceutics, College of Pharmacy, King Saud University, PO Box 2457, Riyadh, 11451, Saudi Arabia. E-mail addresses: [email protected] (M. Raish), [email protected] (K.M. Alkharfy). http://dx.doi.org/10.1016/j.biopha.2017.04.015 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved.
This plant has been used to treat epileptic disorders [8]. The roots and rhizomes are used to treat different disorders such as uterine diseases, epileptic disorders, nervine tonic, and as blood purifier, while the seeds have purgative properties [7,8]. PE constituents include triterpenes, monoterpene phenolics, glycosides, and anthraquinone. The biological activities that have been reported for these phytoconstituents include anticoagulant and cardioprotective, inhibition of b-glucuronidase and antioxidant activity, and relaxation of airway obstruction [8–10]. Herbal medicines, dietary supplements, and other foods may interact with CBZ pharmacokinetically and/or pharmacodynamically, leading to potential clinical concerns. The use of phytomedicines has become increasingly popular; therefore, the incidence of patients taking CBZ with herbal and dietary supplements is high, and it is necessary to report the safety issues of such concurrent use [11,12]. There are no reports hitherto about the pharmacokinetic interactions between CBZ and PE. Since PE is one of the herbs used as an adjuvant therapy by some epileptic patients, it may be administered concomitantly with CBZ in clinical situations. Therefore, the present study was conducted to investigate the
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effects of PE on the pharmacokinetics of CBZ and to determine the possible mechanism of interaction between PE and CBZ. 2. Experimental 2.1. Drugs, chemicals, and plant materials CBZ (C4024) and omeprazole (IS, O104) were purchased from Sigma-Aldrich (St Louis, MO, USA). Acetonitrile (361881) and methanol (261091) (HPLC grade) were obtained from Panreac Chemicals (Barcelona, Spain), while potassium dihydrogen phosphate (P34783/151) was procured from Winlab Ltd. (Maidenhead, Berkshire, UK). Milli-Q water was produced in our laboratory by a purification system (Millipore Corp., Billerica, MA, USA). AntiCYP3A2 (LS-C36108) and CYP2C11 (LS-C64214) antibodies were purchased from LifeSpan Biosciences, Inc. (Seattle, WA, USA). All chemical reagents used were of analytical grade. PE roots were purchased from a local market in Riyadh, Saudi Arabia, and were authenticated by an herbarium. Extraction of the roots was conducted according to previously reported methods [8,13,14]. Briefly, the powdered roots of PE were extracted using a Soxhlet apparatus (80 C) with 90% ethyl alcohol under boiling temperatures for 6 h, and then filtered through a mesh cloth to collect the extract. The extract was then concentrated under reduced pressure at 45 C to obtain the crude extract. 2.2. Animals Healthy male Wistar rats (180–200 g) were obtained from the Central Animal House Facility of the College of Pharmacy, King Saud University (Riyadh, Saudi Arabia), and were divided into two groups (n = 6) and placed in plastic animal cages with a 12-h light/ dark cycle (25 2 C) in accordance with the animal facilities guidelines (Clearance No. 396; March 21, 2014). The rats were provided water ad libitum and fed standard rat chow diet. The animals were acclimatized to laboratory conditions for a week prior to experiments. 2.3. Pharmacokinetic studies The animals were divided into two groups (n = 6 each), and fasted for 12 h before the experiment, while water was allowed ad libitum. Group I rats were treated with normal saline orally for 6 days and received CBZ (80 mg/kg p.o.) on day 7. Group II rats were treated with an oral dose of PE extract (200 mg/kg) for 7 consecutive days and received CBZ (80 mg/kg p.o.) on day 7, one hour after PE administration; normal controls were run in parallel. Blood samples were collected from retro-orbital plexus in tubes containing di-sodium EDTA at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 12 and 24 h after CBZ administration. Plasma was separated by centrifugation at 2500 g for 10 min and transferred to pre-labeled Eppendorf tubes for subsequent simultaneous analysis of CBZ by RP-HPLC. At the end of the experiments, the rats were anesthetized under light ether and euthanized, and liver tissue samples were excised for western blotting.
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filtered through a 0.45 mm Millipore filter and degassed prior to use. The flow rate of the mobile phase was set at 0.8 ml/min. CBZ was analyzed at a wavelength of 285 nm. The chromatographic identification and quantification was carried out at room temperature (25 1 C). A Symmetry1 C18 (5 mm, 3.9 150 mm) column was used to elute the compounds of interest at a lmax = 254 nm. Signal output was carried out by using Lab Solutions 32 software, version 3.05 (Shimadzu, Tokyo, Japan). The analysis of the non-compartmental pharmacokinetic parameters was performed using PK Solver software (version 1.0). The calculated parameters were: area under plasma concentration-time curve (AUC) using the linear trapezoid method; area under the first moment curve (AUMC); mean residence time (MRT), where MRT = AUMC/AUC; volume of distribution (Vz), where Vz = (dose/AUC x lz); total clearance (CL), where CL = dose/AUC, and absorption rate constant (Ka), where Ka = (1/MAT). The terminal elimination rate constant (lz) was calculated from the slope of the logarithm of the plasma concentration versus time. The apparent elimination half-life (T1/2) was calculated as ln2/lz. The maximum plasma concentration (Cmax) and time to maximum concentration (Tmax) were determined empirically directly from the time-concentration curve. 2.5. CYP3A2 and CYP2C11 hepatic protein expression in rats Western blot analysis were performed according to Towbin et al. [16] with minor modification to quantify the effect of PE on hepatic expression of CYP3A2, CYP2C11, and b-actin. Hepatic protein (25 mg) was denatured by diluting with loading buffer and boiling for 5 min at 100 C. Each sample was loaded onto a 10% SDSpolyacrylamide gel and subjected to electrophoresis at 100 V for 2 h. Separated proteins were transferred to trans-Blot PVDF membrane (0.45 mm) in a buffer containing 25 mM Tri–HCl, 192 m glycine, and 20% methanol (v/v). The blots were blocked overnight at 4 C in a solution containing 5% skim milk powder, 2% bovine serum albumin, and 0.5% Tween-20 in Tris-buffered saline (TBS) buffer. The blots were rinsed three times in wash buffer (0.1% Tween-20 in TBS). Membranes were incubated with primary antibodies against CYP3A2 (1/800, LS-C36108), CYP2C11 (1/1000, LS-C64214) and b-actin (1/1000, sc-47778) for 2 h at 4 C in TBS containing 0.01% sodium azide and 0.05% Tween-20. Blots were rinsed three times with wash buffer, followed by incubation with horseradish peroxidase-conjugated anti-rabbit or anti-mouse IgG secondary antibodies (1/5000 dilution) for 1 h at room temperature and washed. Bands were visualized using LuminataTM Western Chemiluminescent HRP Substrates (Millipore, Billerica, MA, USA) and a densitometric analysis of the immunoblots was performed using LI-COR C-DiGit Blot Scanners (Lincoln, NE, USA). 2.6. Statistical analysis The data are expressed as mean standard error of mean (SEM). The significance was determined by applying Students ttest or one-way analysis of variance as appropriate; p values of < 0.05 were considered significant.
2.4. Bioassay and pharmacokinetic analysis 3. Results CBZ plasma concentrations were measured using a validated high-performance liquid chromatographic analytical method previously reported by our laboratory [15]. Briefly, the HPLC (Shimadzu, Kyoto, Japan) system consisted of a SIL 20A with auto sampler, model LC 20AD dual piston solvent delivery pump, model SPD 20A dual UV detector, and vacuum degasser. The mobile phase ratio containing methanol: acetonitrile: potassium dihydrogen phosphate buffer (20 mM) in the ratio of 65:2:33 v/v/v that was
3.1. Effect of PE on CBZ pharmacokinetics The HPLC chromatograms of both PE extract and CBZ are shown in Fig. 1. The estimated pharmacokinetic parameters of CBZ alone and co-administered with PE are listed in Table 1 and Fig. 2. The Cmax of oral administration of CBZ in rats was found to be 4.82 0.20 mg/ml with a Tmax at 2 h; in animals co-administered
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Fig. 1. HPLC chromatogram of plasma sample from a rat administered with both PE (200 mg/kg p.o. for seven days) extract and Carbamazepine (80 mg/kg p.o.).
PE, Cmax of CBZ was 5.52 0.93 mg/ml with a Tmax of approximately 2 h. The co-administration of PE with CBZ showed increases in AUC0–1 by approximately 40%, T1/2 by 44%, and MRT by 33% as compared to CBZ alone (p < 0.05). Conversely, the calculated Kel, CL/F, and Vz decreased by 31%, 33% and 3%, respectively. This decrease in CL/F resulted in a significant increase in CBZ residence time by approximately 33% after a single administration compared to rats that did not receive PE (p < 0.05). 3.2. Effect of PE on CYP3A2 and CYP2C11 hepatic protein expression in rats Hepatic expression of CYP3A2 and CYP2C11 proteins were markedly decreased following PE treatment as compared with b-actin controls (Fig. 3). CBZ treatment caused a significant increase in CYP3A2 and CYP2C11 protein levels compared to normal controls by 3.2 and 2.7-fold, respectively (p < 0.05). In rats treated with PE, there was an approximate 50% inhibition of CBZinduced CYP3A2 and CYP2C11 expression (p < 0.05). 4. Discussion Concomitant use of herbal medicine may mimic, augment, or reduce the activity of drugs [17]. Antiepileptic therapy is usually prolonged and requires monitoring of drug concentration to reduce the risk of side effects [18]. CBZ is a narrow-spectrum antiepileptic drug and is subject to potential herb-drug or fooddrug interactions [19]. Patients are often uninformed of possible herb-drug interactions, and many do not consider herbal medicines as drugs. Consequently, they do not inform their
healthcare providers about a concomitant use of herbal products [20]. PE roots have been used to treat epilepsy over many centuries [10]. The prevalent chemical moieties in PE are monoterpene glycosides, triterpenes, anthraquinone, phenolics, and oligo stilbenes [10]. Taking into account the high prevalence of PE use for epilepsy in the subcontinent, the risk of the co-administration of PE with narrow-therapeutic antiepileptics such as CBZ cannot be underestimated. To the best of our knowledge, this is the first report that explores the effect of PE on the pharmacokinetics of CBZ after oral administration using an animal model. The commonly used oral dose of PE is about 6 g per day; therefore, we calculated an equivalent rat dose [21]. CBZ is an important substrate for CYP3A4 and CYP2C9 in humans, and CYP3A2 and CYP2C11 in rats [22,23]. The overall rate of biotransformation of CBZ in rats is distinctly different from that in humans; the metabolic clearance is more than 10-fold faster in rats [24,25]. Therefore, the current study employed 24-h experiments in rats. Prior treatment with PE for seven days caused an escalation in the Cmax, AUC0-1, and T1/2 of CBZ, and a reduction in its clearance. This indicates a decline in CBZ metabolism following the co-administration of PE in rats. CBZ is largely metabolized in the liver with only 5% of the drug eliminate unchanged [26]. The primary path of metabolism is conversion to an active metabolite CBZ 10.11-epoxide (CBZ-E), which has the same efficacy as the parent compound [22]. This reaction in humans is mainly catalyzed by CYP3A4, although CYP2C8 also plays a role, and participation of CYP3A5 has also been proposed [27,28]. Drugs that inhibit the metabolism of CBZ frequently lead to augmentation of plasma levels and signs of toxicity. Grapefruit, kinnow,
Table 1 Non-compartmental pharmacokinetic parameters of CBZ and CBZ with PE following oral administration in rats. Parameter
CBZ
CBZ + PE
% Change
p-value
lz (1/h)
0.15 0.01 4.76 0.31 2.00 0.00 4.82 0.20 35.20 1.97 36.77 2.37 278.60 32.51 7.47 0.41 14.95 0.26 2.21 0.15
0.10 0.004 6.84 0.30 2.00 0.00 5.52 0.09 49.17 0.45 54.46 0.98 544.58 29.82 9.97 0.37 14.48 0.41 1.47 0.02
31.14 43.72 0.00 14.61 39.67 48.12 95.47 33.46 3.14 33.54
0.0012 0.0007 1.00 0.0065 0.0001 0.0001 0.0002 0.001 0.1823 0.0005
T1/2 (h) Tmax (h) Cmax (mg/ml) AUC0-t (mg/ml*h) AUC0-1 (mg/ml*h) AUMC0-1 (mg/ml*h2) MRT0-1 (h) Vz/F ((mg/kg)/(mg/ml)) CL/F ((mg/kg)/(mg/ml)/h)
Fig. 2. A representative plasma concentration-time curve of CBZ (80 mg/kg p.o.) administered with/without PE (200 mg/kg p.o. for seven days) in rats.
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Fig. 3. Expression of hepatic CYP3A2 and CYP2C11 protein expression in rats following CBZ administration with and without PE treatment. All values represent mean SEM. *p < 0.05 (Control); #p < 0.05 (CBZ); ANOVA, followed by Dunnett's multiple comparison test.
pomegranate, and star fruit juice have the ability to increase Cmax and AUC of CBZ due to inhibition of CYP3A4 [25,29–31]. The Chinese herbs Hu-gan-ning pian, ginkgo biloba, Xiao-yao-san, and Jia-wei-xiao-yao-san decreased the plasma level and oral bioavailability of CBZ by enhancing the rate of metabolism of CBZ through CYP3A4 induction [32,33]. Drugs that inhibit metabolism of CBZ frequently lead to accumulation of CBZ and signs of toxicity, whereas drugs that enhance the metabolism of CBZ can lead to no effect or sub-therapeutic effect. Moreover, the principle metabolite of CBZ, CBZ-10,11 epoxide, is pharmacologically active and may contribute to the toxicities of CBZ [34]. Some PE constituents, including monoterpene glycosides, triterpenes, anthraquinone, phenolics and oligo stilbenes, are known to be potent inhibitors of CYP3A and CYP2C9 [35,36]. These compounds function as competitive substrates for cytochrome P450 and therefore block the metabolism of CBZ. A detailed biochemical mechanism has been established with a comprehensive kinetic study [37–39]. In order to elucidate the possible mechanism, we performed western blot analysis, which clearly demonstrated a significant inhibition of CYP3A2 and CYP2C11 hepatic protein expression in PE-treated rats. It is an established fact that CBZ itself induces CYP3A and CYP2C protein expression [22,40]. The current study has shown that PE interferes with CBZ pharmacokinetics by increasing Cmax, AUC0-1 and T1/2, and a reducing its clearance. These results are in agreement with several pharmacokinetic studies where the bioavailability of CBZ is enhanced due to interactions with CYP3A inhibitors [25,41]. The mechanism might also involve the site of CBZ absorption in the intestine. Thus, increased oral absorption of CBZ with PE co-administration in rats could be the result , at least partially, of a modulation of P-glycoprotein activity. However, it is still under debate whether CBZ is a substrate for Pglycoprotein [36,42].
5. Conclusion The present study demonstrated that PE extract has the potential to alter the pharmacokinetics of CBZ by a significant reduction in protein expression of CYP3A2 and CYP2C11 (50% and
55.55%, respectively). This was associated with a substantial reduction in CBZ clearance and an increase in its AUC and T1/2. Therefore, the co-administration of PE with CBZ should be viewed cautiously. Further studies in humans are needed to determine the clinical relevance of such observations. Conflict of interest The authors declare that they have no conflicts of interest. Acknowledgment The author would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding through research group number (RG# 1435-017). References [1] N.F. Moran, K. Poole, G. Bell, J. Solomon, S. Kendall, M. McCarthy, D. McCormick, L. Nashef, J. Sander, S.D. Shorvon, Epilepsy in the United Kingdom: seizure frequency and severity, anti-epileptic drug utilization and impact on life in 1652 people with epilepsy, Seizure 13 (6) (2004) 425–433. [2] L.P. Hsieh, C.Y. Huang, Antiepileptic drug utilization in Taiwan: analysis of prescription using National Health Insurance database, Epilepsy Res. 84 (1) (2009) 21–27. [3] I. Bielen, A. Sruk, M. Planjar-Prvan, L. Cvitanovic-Sojat, M. Kosicek, B. BergmanMarkovic, R. Baraba, S. Butkovic-Soldo, Age-related pattern of the antiepileptic drug utilization in active epilepsy: a population-based survey, Coll. Antropol. 33 (2) (2009) 659–663. [4] Z. Tolou-Ghamari, M. Zare, J.M. Habibabadi, M.R. Najafi, A quick review of carbamazepine pharmacokinetics in epilepsy from 1953 to 2012, J. Res. Med. Sci. 18 (Suppl. (1)) (2013) S81–5. [5] T. Okuma, A. Kishimoto, A history of investigation on the mood stabilizing effect of carbamazepine in Japan, Psychiatry Clin. Neurosci. 52 (1) (1998) 3–12. [6] A.L. Grzesiak, M. Lang, K. Kim, A.J. Matzger, Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I, J. Pharm. Sci. 92 (11) (2003) 2260–2271. [7] T.A. Ketter, R.M. Post, K. Worthington, Principles of clinically important drug interactions with carbamazepine. Part I, J. Clin. Psychopharmacol. 11 (3) (1991) 198–203. [8] AZSM, S.S. Shadab Ahmad Pathan, F.J. Ahmad, S.S. Jamil, R.K. Khar, Effect of repeated administration of paeonia emodi wall root extract in experimental models of epilepsy and behavior, J. Pharmacol. Toxicol. 7 (2012) 64–74. [9] A. Ahmad, K.M. Alkharfy, T.A. Wani, M. Raish, Application of Box-Behnken design for ultrasonic-assisted extraction of polysaccharides from Paeonia emodi, Int. J. Biol. Macromol. 72 (2015) 990–997.
698
M. Raish et al. / Biomedicine & Pharmacotherapy 90 (2017) 694–698
[10] B.A. Zargar, M.H. Masoodi, B.A. Khan, S. Akbar, Paeonia emodi Royle: ethnomedicinal uses, phytochemistry and pharmacology, Phytochem. Lett. 6 (2) (2013) 261–266. [11] L.C. Chen, Y.F. Chen, L.L. Yang, M.H. Chou, M.F. Lin, Drug utilization pattern of antiepileptic drugs and traditional Chinese medicines in a general hospital in Taiwan—a pharmaco-epidemiologic study, J. Clin. Pharm. Ther. 25 (2) (2000) 125–129. [12] K. Liow, E. Ablah, J.C. Nguyen, T. Sadler, D. Wolfe, K.D. Tran, L. Guo, T. Hoang, Pattern and frequency of use of complementary and alternative medicine among patients with epilepsy in the midwestern United States, Epilepsy Behav. 10 (4) (2007) 576–582. [13] M.A. Taous Khan, Hamayun Khan, Mir Azam Khan, Biological activities of aerial parts of Paeonia emodi Wall, Afr. J. Biotechnol. 4 (11) (2005) 1313–1316. [14] T. Khan, M. Ahmad, M. Nisar, M.A. Lodhi, M.I. Choudhary, Enzyme inhibition and radical scavenging activities of aerial parts of Paeonia emodi Wall (Paeoniaceae), J. Enzyme Inhib. Med. Chem. 20 (3) (2005) 245–249. [15] F.I.A.-J. Khalid M. Alkharfy, Mohd. Aftab Alam, Abdullah M. Al-Mohizea,, H.M.K. Saleh A. Al-Suwayeh, RaoM. A. Khan and Iqbal Muzaffar, Lepidium Sativum but not Nigella Sativa Affects Carbamazepine Disposition in an Animal Model, Drug Metabolism Letters, 2013, 7, 47–51 7 (2013) 47–51. [16] H. Towbin, T. Staehelin, J. Gordon, Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications, Proc. Natl. Acad. Sci. U. S. A. 76 (9) (1979) 4350–4354. [17] A. Fugh-Berman, E. Ernst, Herb-drug interactions: review and assessment of report reliability, Br. J. Clin. Pharmacol. 52 (5) (2001) 587–595. [18] S.Y. Fong, Q. Gao, Z. Zuo, Interaction of carbamazepine with herbs, dietary supplements, and food: a systematic review, Evid. Based Complement. Alternat. Med. 2013 (2013) 898261. [19] T.a. Ketter, R.m. post, K. worthington, Principles of clinically important drug interactions with carbamazepine. Part I, J. Clin. Psychopharmacol. 11 (3) (1991) 198–202. [20] C. Tarirai, A.M. Viljoen, J.H. Hamman, Herb-drug pharmacokinetic interactions reviewed, Expert Opin. Drug Metab. Toxicol. 6 (12) (2010) 1515–1538. [21] S. Reagan-Shaw, M. Nihal, N. Ahmad, Dose translation from animal to human studies revisited, FASEB J. 22 (3) (2008) 659–661. [22] R.E. Pearce, W. Lu, Y. Wang, J.P. Uetrecht, M.A. Correia, J.S. Leeder, Pathways of carbamazepine bioactivation in vitro. III. The role of human cytochrome P450 enzymes in the formation of 2,3-dihydroxycarbamazepine, Drug Metab. Dispos. 36 (8) (2008) 1637–1649. [23] T. Tateishi, M. Asoh, H. Nakura, M. Watanabe, M. Tanaka, T. Kumai, S. Kobayashi, Carbamazepine induces multiple cytochrome P450 subfamilies in rats, Chem. Biol. Interact. 117 (3) (1999) 257–268. [24] J. Faigle, Carbamazepine: chemistry and biotransformation, Antiepileptic Drugs (1995) 499–513. [25] M. Hidaka, M. Okumura, K. Fujita, T. Ogikubo, K. Yamasaki, T. Iwakiri, N. Setoguchi, K. Arimori, Effects of pomegranate juice on human cytochrome p450 3A (CYP3A) and carbamazepine pharmacokinetics in rats, Drug Metab. Dispos. 33 (5) (2005) 644–648. [26] K.A. Kim, S.O. Oh, P.W. Park, J.Y. Park, Effect of probenecid on the pharmacokinetics of carbamazepine in healthy subjects, Eur. J. Clin. Pharmacol. 61 (4) (2005) 275–280.
[27] S.I. Hung, W.H. Chung, Z.S. Liu, C.H. Chen, M.S. Hsih, R.C. Hui, C.Y. Chu, Y.T. Chen, Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese, Pharmacogenomics 11 (3) (2010) 349–356. [28] B.M. Kerr, K.E. Thummel, C.J. Wurden, S.M. Klein, D.L. Kroetz, F.J. Gonzalez, R.H. Levy, Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10,11-epoxide formation, Biochem. Pharmacol. 47 (11) (1994) 1969–1979. [29] S.K. Garg, V.K. Bhargava, H. James, N. Kumar, S. Prabhakar, Influence of kinnow juice on the bioavailability of carbamazepine in healthy male volunteers, Neurol. India 46 (3) (1998) 229–231. [30] S.K. Garg, N. Kumar, V.K. Bhargava, S.K. Prabhakar, Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy, Clin. Pharmacol. Ther. 64 (3) (1998) 286–288. [31] M. Hidaka, M. Okumura, T. Ogikubo, H. Kai, K.I. Fujita, T. Iwakiri, K. Yamasaki, N. Setoguchi, N. Matsunaga, K. Arimori, Transient inhibition of Cyp3A in rats by star fruit juice, Drug Metab. Dispos. 34 (3) (2006) 343–345. [32] Z.J. Zhang, W.H. Kang, Q. Li, Q.R. Tan, The beneficial effects of the herbal medicine free and easy Wanderer Plus (FEWP) for mood disorders: doubleblind, placebo-controlled studies, J. Psychiatr. Res. 41 (10) (2007) 828–836. [33] C.R. Harish, M. Rajkumar, C. Veeresham, Pharmacokinetic interaction of ginkgo biloba with carbamazepine, Planta Med. 75 (4) (2009) 454–454. [34] Y.C. Wong, S. Qian, Z. Zuo, Regioselective biotransformation of CNS drugs and its clinical impact on adverse drug reactions, Expert Opin. Drug Met. 8 (7) (2012) 833–854. [35] M. Miyazawa, M. Shindo, T. Shimada, Roles of cytochrome P450 3A enzymes in the 2-hydroxylation of 1 4-cineole, a monoterpene cyclic ether, by rat and human liver microsomes, Xenobiotica 31 (10) (2001) 713–723. [36] L. Basheer, Z. Kerem, Interactions between CYP3A4 and dietary polyphenols, Oxid. Med. Cell. Longevity 2015 (2015) 854015. [37] J. Ehlting, B. Hamberger, R. Million-Rousseau, D. Werck-Reichhart, Cytochromes P450 in phenolic metabolism, Phytochem. Rev. 5 (2–3) (2006) 239–270. [38] Y. Kapelyukh, M.J. Paine, J.-D. Maréchal, M.J. Sutcliffe, C.R. Wolf, G.C. Roberts, Multiple substrate binding by cytochrome P450 3A4: estimation of the number of bound substrate molecules, Drug Metab. Dispos. 36 (10) (2008) 2136–2144. [39] J. Zhao, J. Zhao, S. Franzen, The regulatory implications of hydroquinone for the multifunctional enzyme dehaloperoxidase-hemoglobin from Amphitrite ornata, J. Phys. Chem. B 117 (47) (2013) 14615–14624. [40] N. Ohnishi, Y. Yonekawa, S. Nakasako, K. Nagasawa, T. Yokoyama, M. Yoshioka, K. Kuroda, Studies on interactions between traditional herbal and Western medicines. I. Effects of Sho-seiryu-to on the pharmacokinetics of carbamazepine in rats, Biol. Pharm. Bull. 22 (5) (1999) 527–531. [41] S.K. Garg, N. Kumar, V.K. Bhargava, S.K. Prabhakar, Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy, Clin. Pharmacol. Ther. 64 (3) (1998) 286–288. [42] E.J. Wang, M. Barecki-Roach, W.W. Johnson, Elevation of P-glycoprotein function by a catechin in green tea, Biochem. Biophys. Res. Commun. 297 (2) (2002) 412–418.