312 Original Article
Authors
F. I. Al-Jenoobi, A. Ahad, M. Raish, A. M. Al-Mohizea, M. A. Alam
Affiliation
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
Key words
Abstract
▶ bioavailability ● ▶ cytochrome P4501A ● ▶ disposition ● ▶ herb-drug interaction ●
▼
Aim: The present study was conducted to investigate the effect of commonly used herb Commiphora myrrha on the pharmacokinetic profile of theophylline (narrow therapeutic index drug) in rabbits. Methods: In the experimental groups, theophylline (16 mg/kg) was given orally to the rabbits. Where aqueous saline suspension of Commiphora myrrha (176 mg/kg, p.o.), was given to the rabbits and the blood samples were withdrawn at different time intervals (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h) from marginal ear vein after
Introduction
▼ received 20.03.2014 accepted 26.05.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1382032 Published online: July 3, 2014 Drug Res 2015; 65: 312–316 © Georg Thieme Verlag KG Stuttgart · New York ISSN 2194-9379 Correspondence Dr. A. Ahad, Assistant professor Department of Pharmaceutics College of Pharmacy, King Saud University P.O. Box 2457 Riyadh 11451 Saudi Arabia Tel.: + 966/557/124 812 Fax: + 966/01/4676 295 [email protected] [email protected]
Medicinal plants have been used since ancient times in almost all cultures as a source of medicine. The comparatively less side effects of herbal medicines in comparison with modern allopathic drugs have led to an exploration of the potential for the concurrent use of herbs with modern drugs in clinical application [1]. According to the World Health Organization (WHO), the use of herbal drugs throughout the world has increased tremendously [2–5]. In many countries, the herbal medicines are being used progressively by the general community on a self-selection basis to either replace or complement modern medicines [6]. It is thus very likely that these herbal medicines may be taken concurrently with conventional drugs. The global increase in the popularity of alternative medicines has raised renewed concerns regarding herb-drug interactions. In recent years, the issue of herbal medicine-drug interactions has generated significant concern, as such interactions can increase the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index (e. g. theophylline) [7, 8].
Al-Jenoobi FI et al. Herb-Drug Interaction Study … Drug Res 2015; 65: 312–316
dosing and theophylline in plasma was analyzed by HPLC method. Results: It was observed that there a significant differences in the Cmax, AUC, AUMC, t1/2, and MRT of theophylline when coadministered with Commiphora myrrha which indicate that the herb affect the metabolism and elimination when coadministered with theophylline. Conclusion: Our results suggested that concurrent use of investigated herb alters the pharmacokinetics of theophylline. Confirmation of these results in human studies will warrant changes in theophylline dose or frequency when coadministered with herb under consideration.
The interactive properties of some commonly used herb with prescribed medications have not been previously investigated. In particular, there is a lack of information regarding the effect of investigated herb on the activity of cytochrome P450 (CYP) enzymes. Given the fact that selfmedication is a prevalent practice is globally, more information about possible drug interactions with local herbal products is of a critical importance. ▶ Fig. 1) is a methylxanthine derivTheophylline (● ative with diuretic, smooth muscle relaxant, bronchial dilation, cardiac and central nervous system stimulant activities [9]. The plasma protein binding of the theophylline is about 40 % and half-life is about 8 h. Oral absorption of theophylline is almost complete; with peak plasma concentrations generally achieved 2 h after administration, although this can be influenced by co-administered medications [10, 11]. Theophylline is eliminated almost exclusively by CYP mediated hepatic oxidation, predominantly to 1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine by CYP1A2, and, to a lesser extent, to 1,3-dimethyluric acid by CYP2E1 [12, 13]. Hence, it could be expected that the
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Investigating the Potential Effect of Commiphora myrrha on the Pharmacokinetics of Theophylline, a Narrow Therapeutic Index Drug
Original Article 313
Fig. 1 The chemical structure of theophylline.
Animals 10 healthy rabbits weighing between 3.0 and 4.0 kg were obtained after the study was duly approved by the Experimental Animal Care Center, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Animals were maintained in accordance with the recommendations of the ‘Guide for the Care and Use of Laboratory Animals approved by the center (NIH publications no. 80-23; 1996). All animals were maintained under standard laboratory conditions at room temperature. The animals were given pellet diet with water ad libitum and fasted overnight prior to the experiments.
pharmacokinetic parameters of theophylline could be changed in the pretreatment of herbal medicine which affects the activity of CYP1A2. Theophylline has been characterized by a narrow therapeutic index with the therapeutic concentration ranges of 5–20 μg/mL [14]. Therefore, herb-drug or drug-drug interaction may sensitively affect the therapeutics of theophylline. Inhibition of CYPlA2 activity may increase plasma theophylline concentration by inhibiting hepatic clearance and may contribute to the emergence of adverse effects. In contrast, induction of cytochrome isozymes may reduce plasma theophylline to sub therapeutic concentration. The present study is designed to investigate the effect of commonly used herb like Commiphora myrrha on the pharmacokinetic of narrow therapeutic index drug such as theophylline in rabbit. Briefly, myrrh is a dried oleo-gum resin of Commiphora myrrha (Burseraceae). Myrrh contains volatile oil (1.5–17 %) composed of limonene, dipentene, pinene, eugenol, cinnamaldehyde, cuminaldehyde, cumic alcohol, m-cresol, cadinene, curzerene (11.9 %), curzerenone (11.7 %), furanoeudesma-1,3diene (12.5 %), up to 40 % resins consisting of α-, β-, and γ-commiphoric acids, commiphorinic acid [15]. Myrrh oil is used as a fragrance component or fixative in soaps, detergents, creams, lotions, and perfumes. It can be used as a flavor component in major food products [16]. In Ayurveda medicine it is used for its rejuvenating properties. It also has a historic place in Chinese medicine. It is used to treat infected wounds; bronchial complaints such as asthma, sinusitis and minor skin inflammations as well as inflammation of the throat, gums and mouth, including mouth ulcers, gingivitis and stomatitis [17].
Materials and Methods
▼
Chemicals and reagents Theophylline was obtained from BASF, Germany. High performance liquid chromatography (HPLC)-grade acetonitrile and methanol were obtained from Fisher Scientific (Leicestershine, UK) and Panreac Quimica (Barcelona, Espana) respectively. All chemicals used were of the highest available commercial purity. Commiphora myrrha was purchased in dry form from local market. HPLC grade solvents were used for HPLC determinations. All aqueous solutions were prepared using purified water filtered by Milli-QR Gradient A10R (Millipore, Molsheim Cedex, France), having pore size 0.22 μm. All other materials are of analytical grade.
In experimental groups, overnight fasted rabbits (n = 5) were placed in individual restrainer. A polyethylene catheter (BD InsyteTM AutoguardTM Winged, Sandym Utah) was inserted into the ear vein of each rabbit to collect blood samples. Theophylline (16 mg/kg, p. o.) was given orally to each rabbit and blood samples (1.0–1.5 mL) were collected into heparinized vacutainer tubes at 0.0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12, 24 and 36 h. In another group, rabbits were treated with saline suspension of Commiphora myrrha (176 mg/kg, p. o.) for the next 8 consecutive days. The animals were fasted overnight after the 7th day treatment. On the morning of, 8th day, the last dose of Commiphora myrrha was administered to the fasted animals. After 1.0 h of the last dose of Commiphora myrrha, theophylline (16 mg/kg, p. o.) was administered, and the same sampling scheme was repeated as described previously. Each collected samples were centrifuged at 12 000 rpm for 10 min. Plasma was separated and stored at − 80 °C until assayed for theophylline by HPLC method.
Bioanalysis of theophylline The HPLC system consisted of Shimadzu’s CTO-20A Prominence column oven, equipped with SPD 20A UV/VIS detector, SIL-20A Auto sampler, CBM-20A communication Bus Module, LC-20AD solvent delivery pump and DGU-20A5 degasser was used for the assay of theophylline. The data was acquired and processed with Shimadzu LC Solution software. The prontosil C-18 column (5 μm, 150 mm × 4.6 mm i.d) was used. The mobile phase consisted of HPLC water/acetonitrile (92: 8 v/v) with pH of 4.2 adjusted with glacial acetic acid (0.5 mL/L), filtered through a 0.45 μm Millipore filter, and degassed prior to use. The flow rate was 1.0 mL/min. Theophylline was analyzed at a wavelength of 272 nm.
Calibration standards and quality control samples Standard stock solutions of theophylline (2.5 mg/mL) and acetaminophen as IS (1 mg/mL) were prepared in methanol. The solutions were stored in a refrigerator below 8 °C and used for 15 days from the date of preparation. Working solutions of theophylline and IS (100 μg/mL) were prepared in methanol: water (50: 50). Working solutions of theophylline and IS (8 μL) were added to drug-free plasma (200 μL) to obtain final concentrations of 0.25, 0.5, 1.25, 2.5, 5.0, 12.5, and 25.0 μg/mL. The quality control samples at 3 different concentrations were also prepared in a similar manner as the calibration standards. Spiked plasma calibration standards and quality control samples were stored at − 80 ± 2 °C until analyzed.
Sample preparation The protein precipitation method was used to prepare samples for analysis [18]. Plasma samples stored at around − 80 °C were Al-Jenoobi FI et al. Herb-Drug Interaction Study … Drug Res 2015; 65: 312–316
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Study design
314 Original Article
thawed at room temperature and vortex for 30 s to ensure homogeneity. To the 200 μL of plasma sample, 8 μL of methanol, 8 μL of IS (100 μg/mL) and 584 μL of zinc sulphate solution (2 %) was added to precipitate protein of the sample. The samples were again vortex mixed gently for 1.5 min and then centrifuged for 10 min at 12 000 rpm. After centrifugation, 700 μL of clear supernatant was transferred into HPLC vials. The 25 μL of each sample was subjected to HPLC-UV analysis.
total body clearance (CL) as dose/AUC0–∞, mean residence time (MRT) is the ratio of AUMC0–36 and AUC0–36 were calculated.
Statistical analysis Data are presented as the mean ± standard deviation (SD). Differences in pharmacokinetic parameters of theophylline before and after pretreatment with herb were assessed by paired t-test using GraphPad Prism version 3.00 for Windows (San Diego, CA, USA). Statistical significance were assumed when p ≤ 0.05.
Pharmacokinetic analysis
Fig. 2 Plasma concentrations vs. time profile of theophylline following an oral administration in rabbits before and after pretreatment with Commiphora myrrha (mean ± SD).
Table 1 Pharmacokinetic parameters of theophylline following an oral administration in rabbits before and after pretreatment with Commiphora myrrha (n = 5. mean ± SD). Parameters
Control
Theophylline +
p-value
Commiphora
Results
▼
The comparison of plasma concentration-time profile of the theophylline when given alone to the animal or along with the ▶ Fig. 2. The calibration curves Commiphora myrrha is shown in ● of theophylline prepared in rabbit plasma was found to be linear with respect to the analyte concentration over the range 0.25– 25 μg/mL. The pharmacokinetic parameters, including Cmax, Tmax, ▶ Table 1. AUC0–36, AUC0–∞, AUMC0–36, Ke and t1/2, are given in ● The rate of theophylline absorption which is represented by the parameter (Cmax) after administration of theophylline alone (control) was found to be 25.38 ± 2.25 μg/mL, and Tmax was 3.80 ± 0.45 h, while group treated with theophylline + Commiphora myrrha produced Cmax and Tmax of 17.29 ± 2.45 μg/mL and 3.80 ± 1.30 h respectively. The Cmax was significantly (p = 0.0062) decreased by 31.88 % after treatment the animals with herb as ▶ Table 1). compared with the Cmax of control group (● It was also observed that AUC0–36, AUC0–∞ and AUMC0–36 of control group was 368.28 ± 23.85 μg/mL/h, 394.92 ± 27.50 μg/mL/h and 4 107.51 ± 418.94 μg/mL/h2, however theophylline + Commiphora myrrha treated group presented 214.29 ± 26.78 μg/mL/h, 219.17 ± 26.73 μg/mL/h and 1 997.68 ± 223.10 μg/mL/h2 of AUC0–36, ▶ Table 1) AUC0–∞ and AUMC0–36 respectively (● . Both Cmax and AUC0–∞ were statistically different before and after Commiphora myrrha treatment in rabbits (p < 0.01). The bioavailability of theophylline was decreased (48.63 ± 9.03 %) when drug was co-administered with Commiphora myrrha. The calculated oral clearance increased by 73 % (CL/F from 43.58 ± 2.68 mL h − 1 to 75.66 ± 9.98 mL h − 1; p = 0.0028), while the estimated oral volume of distribution was increased by 31 % (Vd from 536.39 ± 112.69 mL to 705.33 ± 102.48 mL) but this was not sta▶ Table 1). These parameters have resulted tistically significant (● in significant variation in the half-life of theophylline from 10.61 ± 1.41 h to 7.44 ± 0.39 h for control and herb pretreated group respectively in animals, indicates that Commiphora myrrha affects theophylline metabolism to large extent.
myrrha a
Tmax (h) b Cmax (μg/mL) c AUC0→36 h (μgh/mL) d AUC0→∞ (μg/mL/h) e AUMC0 →36 h (μg/mL/h2) f t1/2 (h) g Ke (h − 1) h MRT (h) i CL/F (mL h − 1) j Vd (mL) a
3.80 ± 0.45 25.38 ± 2.25 368.28 ± 23.85 394.92 ± 27.50 4 107.51 ± 418.94 10.61 ± 1.41 0.066 ± 0.008 11.14 ± 0.58 43.58 ± 2.68 536.39 ± 112.69
3.80 ± 1.30 17.29 ± 2.45 214.29 ± 26.78 219.17 ± 26.73 1 997.68 ± 223.10 7.44 ± 0.39 0.093 ± 0.005 9.34 ± 0.25 75.66 ± 9.98 705.33 ± 102.48
0.9999 0.0062 0.0010 0.0007 0.0007 0.0056 0.0007 0.0022 0.0028 0.0573
Time of peak concentration; b Peak of maximum plasma concentration; c Area
under the concentration time profile curve until last observation; d Area under the concentration time profile curve from time 0 to infinity; e Area under the first moment curve until last observation; f Half-life; g Elimination rate constant; h Mean residence time (MRT); i Total clearance; j Volume of distribution
Al-Jenoobi FI et al. Herb-Drug Interaction Study … Drug Res 2015; 65: 312–316
Discussion and Conclusions
▼
The use of complementary and alternative medicines by asthmatic patients is increasing [19] and most patients consider herbal medicines as safe because they are of natural origin. However, these medicines, which may vary in quality and ingredient content, have the potential to interact with anti-asthmatic drug(s). The interaction of drugs with herbal medicines is a significant safety concern, especially for drugs with narrow therapeutic indices (e. g. theophylline, warfarin and digoxin). Because the pharmacokinetics and/or pharmacodynamics of the drug may be altered by combination with herbal remedies, potentially severe and perhaps even life threatening adverse reactions
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The plasma concentrations were used to construct pharmacokinetic profiles by plotting drug concentration-time curves. To determine the pharmacokinetic parameters, all data were obtained subsequently fed into pharmacokinetic software on Microsoft excel®. The non-compartmental pharmacokinetic parameters such as maximum plasma concentration (Cmax) and time to reach maximum concentration (Tmax), area under the curve from 0 to t (AUC0–36), from 0 to ∞ (AUC0–∞) and area under first moment curve from 0–36 (AUMC0–36), elimination rate constant (Kel) and half-life (t1/2) were calculated. The parameters like volume of distribution (Vd) as (AUMC0–∞/AUC0–∞) × CL and
Original Article 315
mainly metabolized by CYP1A, many CYP1A- metabolized compounds could interact with herb under consideration [29]. Furthermore, our results revealed that Commiphora myrrha could cause decrease in the bioavailability and increase in the elimination rate constant of theophylline per oral. This may pose a negative implication in clinical practice as sub therapeutic concentration of theophylline may easily be reached because of the possibility of decrease in half life and faster drug elimination when theophylline intentionally or unintentionally coadministered with Commiphora myrrha. The significant reduction in AUC as well as decreased in half-life are consistent with an induction of CYP1A enzyme. Based on these results, it was concluded that precaution should be taken to avoid coadministration of Commiphora myrrha with theophylline. Clinical investigations are advised for safe use of Commiphora myrrha with CYP1A substrates.
Acknowledgement
▼
The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group project no. RGP-VPP-268.
Conflict of Interest
▼
All authors have approved the final manuscript and the authors declare that they have no conflicts of interest to disclose.
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Al-Jenoobi FI et al. Herb-Drug Interaction Study … Drug Res 2015; 65: 312–316
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may occur [20]. It is important to be aware of the interaction potency of commonly used herbal medicines in order to avoid a reduction in efficacy and an increase in the side-effects of concomitantly administered drugs [6]. The clinical consequence of interactions may be lack of efficacy, toxic reactions, unexpected effects and unforeseen side effects, it is therefore of major importance for patient safety outcomes [21]. Increased blood levels of drugs, related to a decreased activity of the CYP family of enzymes, could result in signs and symptoms of toxicity that are not apparent normally. Conversely, induction of the above enzymes may cause enhanced catabolism, giving rise to subtherapeutic levels and loss of therapeutic control [22]. Overall, interactions between theophylline, a narrow therapeutic index drug and herbal medicines are poorly described in the literature, clearly more research is required. In this regards, the effect of commonly used herbal medicine like Commiphora myrrha on the pharmacokinetic profile of theophylline in rabbits was conducted. The authors believe this is the very first study to report the herb-drug pharmacokinetic interactions between the Commiphora myrrha with drug under consideration. Theophylline is CYP1A substrate and one of the most commonly used anti-asthmatic drug, thus, there is a significant percentage of population who require this drug in their life time. Theophylline is predominantly metabolized by CYP1A, and to a lesser extent by CYP2E and CYP3A [23]. CYP1A is expressed principally in the liver [24]. CYP1A accounts for about 10–15 % of the total CYP content of human liver and metabolizes some important drugs as well as other compounds such as caffeine, and also activates some procarcinogens to carcinogens [25, 26]. CYP1A plays a role in human tobacco-related cancers [27]. Bachmann et al. [28] provided the evidence that theophylline is metabolized principally by CYP1A. In the pretreatment with the CYP1A inducer, β-naphthoflavone, increased theophylline clearance 4.5-fold, and the CYP1A inhibitor, α-naphthoflavone, significantly attenuated the β-naphthoflavone effect. However, the substrates of CYP2E, CYP2D, CYP3A and CYP4A have also been investigated and the result is that it has no significant effect on theophylline clearance. While the powerful CYP3A inducer clotrimazole did not increase theophylline clearance, troleandomycin, an inhibitor of CYP3A, decreased theophylline clearance by about 25 % only. This study has demonstrated that Commiphora myrrha interfere with the theophylline pharmacokinetic to varying degrees in rabbits. In the present study, no overt toxicity was observed with respect to the general behavior of the animals on concurrent administration of either of the herb or theophylline. Herbtreatment for 7 days caused a decrease in Cmax, t1/2, AUC0→∞, Ke and CL/F. This study suggests that simultaneous administration of Commiphora myrrha with theophylline is likely to result in significant interaction. On the basis of pharmacokinetic parameters, significant modulation was observed in the activity of CYP1A. The markedly decreased Cmax and AUC0–t of theophylline caused by coadministration with Commiphora myrrha indicated that the oral bioavailability of theophylline was significantly reduced. The bioavailability of theophylline was found to be decreased about 48.63 % when it was concurrently administered with investigated herb. In addition, there was a 29.88 % decrease in theophylline t1/2 and apparently, the magnitude of theophylline clearance (73.61 %) increased in rabbits. Similarly the ke change quite significantly (p = 0.0007) following the herb administration in rabbits (0.066 h − 1 to 0.093 h − 1). Since theophylline is
316 Original Article 23 Gu L, Gonzalez FJ, Kalow W et al. Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics 1992; 2: 73–77 24 Tang J, Sun J, Zhang Y et al. Herb-drug interactions: Effect of Ginkgo biloba extract on the pharmacokinetics of theophylline in rats. Food Chem Toxicol 2007; 45: 2441–2445 25 Brosen K. Drug interactions and the cytochrome P450 system. The role of cytochrome P450 1A2. Clin Pharmacokinet 1995; 29 (Suppl 1): 20–25 26 Cupp MJ, Tracy TS. Cytochrome P450: new nomenclature and clinical implications. Am Fam Physician 1998; 57: 107–116 27 Smith TJ, Guo Z, Guengerich FP et al. Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by human cytochrome P450 1A2 and its inhibition by phenethyl isothiocyanate. Carcinogenesis 1996; 17: 809–813 28 Bachmann K, Sanyal G, Potter J et al. In vivo evidence that theophylline is metabolized principally by CYP1A in rats. Pharmacology 1993; 47: 1–7 29 Faber MS, Jetter A, Fuhr U. Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol 2005; 97: 125–134
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14 Qiu F, Wang G, Zhao Y et al. Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers. Br J Clin Pharmacol 2008; 65: 270–274 15 Capasso R, Izzo AA, Pinto L et al. Phytotherapy and quality of herbal medicines. Fitoterapia 2000; 71 (Suppl 1): S58–S65 16 Dolara P, Corte B, Ghelardini C et al. Local anaesthetic, antibacterial and antifungal properties of sesquiterpenes from myrrh. Planta Med 2000; 66: 356–358 17 Massoud A, El Sisi S, Salama O. Preliminary study of therapeutic efficacy of a new fasciolicidal drug derived from Commiphora molmol (myrrh). Am J Trop Med Hyg 2001; 65: 96–99 18 Al-Jenoobi FI, Ahad A, Mahrous GM et al. Effects of fenugreek, garden cress, and black seed on theophylline pharmacokinetics in beagle dogs. Pharmaceutical Biology 2014, doi:10.3109/13880209.2014.91 6312 (Article in press) 19 Ng TP, Wong ML, Hong CY et al. The use of complementary and alternative medicine by asthma patients. Qjm 2003; 96: 747–754 20 Fugh-Berman A. Herb-drug interactions. Lancet 2000; 355: 134–138 21 Landmark CJ, Patsalos PN. Interactions between antiepileptic drugs and herbal medicines. Bol Latinoam Caribe Plant Med 2008; 7: 108– 118 22 Thabrew MI, Munasinghe TM, Chackrewarthi S et al. Possible interaction of herbal tea and carbamazepine. Drug Metabol Drug Interact 2003; 19: 177–187
Al-Jenoobi FI et al. Herb-Drug Interaction Study … Drug Res 2015; 65: 312–316
Authors
F. I. Al-Jenoobi, A. Ahad, M. Raish, A. M. Al-Mohizea, M. A. Alam
Affiliation
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
Key words
Abstract
▶ bioavailability ● ▶ cytochrome P4501A ● ▶ disposition ● ▶ herb-drug interaction ●
▼
Aim: The present study was conducted to investigate the effect of commonly used herb Commiphora myrrha on the pharmacokinetic profile of theophylline (narrow therapeutic index drug) in rabbits. Methods: In the experimental groups, theophylline (16 mg/kg) was given orally to the rabbits. Where aqueous saline suspension of Commiphora myrrha (176 mg/kg, p.o.), was given to the rabbits and the blood samples were withdrawn at different time intervals (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h) from marginal ear vein after
Introduction
▼ received 20.03.2014 accepted 26.05.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1382032 Published online: July 3, 2014 Drug Res 2015; 65: 312–316 © Georg Thieme Verlag KG Stuttgart · New York ISSN 2194-9379 Correspondence Dr. A. Ahad, Assistant professor Department of Pharmaceutics College of Pharmacy, King Saud University P.O. Box 2457 Riyadh 11451 Saudi Arabia Tel.: + 966/557/124 812 Fax: + 966/01/4676 295 [email protected] [email protected]
Medicinal plants have been used since ancient times in almost all cultures as a source of medicine. The comparatively less side effects of herbal medicines in comparison with modern allopathic drugs have led to an exploration of the potential for the concurrent use of herbs with modern drugs in clinical application [1]. According to the World Health Organization (WHO), the use of herbal drugs throughout the world has increased tremendously [2–5]. In many countries, the herbal medicines are being used progressively by the general community on a self-selection basis to either replace or complement modern medicines [6]. It is thus very likely that these herbal medicines may be taken concurrently with conventional drugs. The global increase in the popularity of alternative medicines has raised renewed concerns regarding herb-drug interactions. In recent years, the issue of herbal medicine-drug interactions has generated significant concern, as such interactions can increase the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index (e. g. theophylline) [7, 8].
Al-Jenoobi FI et al. Herb-Drug Interaction Study … Drug Res 2015; 65: 312–316
dosing and theophylline in plasma was analyzed by HPLC method. Results: It was observed that there a significant differences in the Cmax, AUC, AUMC, t1/2, and MRT of theophylline when coadministered with Commiphora myrrha which indicate that the herb affect the metabolism and elimination when coadministered with theophylline. Conclusion: Our results suggested that concurrent use of investigated herb alters the pharmacokinetics of theophylline. Confirmation of these results in human studies will warrant changes in theophylline dose or frequency when coadministered with herb under consideration.
The interactive properties of some commonly used herb with prescribed medications have not been previously investigated. In particular, there is a lack of information regarding the effect of investigated herb on the activity of cytochrome P450 (CYP) enzymes. Given the fact that selfmedication is a prevalent practice is globally, more information about possible drug interactions with local herbal products is of a critical importance. ▶ Fig. 1) is a methylxanthine derivTheophylline (● ative with diuretic, smooth muscle relaxant, bronchial dilation, cardiac and central nervous system stimulant activities [9]. The plasma protein binding of the theophylline is about 40 % and half-life is about 8 h. Oral absorption of theophylline is almost complete; with peak plasma concentrations generally achieved 2 h after administration, although this can be influenced by co-administered medications [10, 11]. Theophylline is eliminated almost exclusively by CYP mediated hepatic oxidation, predominantly to 1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine by CYP1A2, and, to a lesser extent, to 1,3-dimethyluric acid by CYP2E1 [12, 13]. Hence, it could be expected that the
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Investigating the Potential Effect of Commiphora myrrha on the Pharmacokinetics of Theophylline, a Narrow Therapeutic Index Drug
Original Article 313
Fig. 1 The chemical structure of theophylline.
Animals 10 healthy rabbits weighing between 3.0 and 4.0 kg were obtained after the study was duly approved by the Experimental Animal Care Center, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Animals were maintained in accordance with the recommendations of the ‘Guide for the Care and Use of Laboratory Animals approved by the center (NIH publications no. 80-23; 1996). All animals were maintained under standard laboratory conditions at room temperature. The animals were given pellet diet with water ad libitum and fasted overnight prior to the experiments.
pharmacokinetic parameters of theophylline could be changed in the pretreatment of herbal medicine which affects the activity of CYP1A2. Theophylline has been characterized by a narrow therapeutic index with the therapeutic concentration ranges of 5–20 μg/mL [14]. Therefore, herb-drug or drug-drug interaction may sensitively affect the therapeutics of theophylline. Inhibition of CYPlA2 activity may increase plasma theophylline concentration by inhibiting hepatic clearance and may contribute to the emergence of adverse effects. In contrast, induction of cytochrome isozymes may reduce plasma theophylline to sub therapeutic concentration. The present study is designed to investigate the effect of commonly used herb like Commiphora myrrha on the pharmacokinetic of narrow therapeutic index drug such as theophylline in rabbit. Briefly, myrrh is a dried oleo-gum resin of Commiphora myrrha (Burseraceae). Myrrh contains volatile oil (1.5–17 %) composed of limonene, dipentene, pinene, eugenol, cinnamaldehyde, cuminaldehyde, cumic alcohol, m-cresol, cadinene, curzerene (11.9 %), curzerenone (11.7 %), furanoeudesma-1,3diene (12.5 %), up to 40 % resins consisting of α-, β-, and γ-commiphoric acids, commiphorinic acid [15]. Myrrh oil is used as a fragrance component or fixative in soaps, detergents, creams, lotions, and perfumes. It can be used as a flavor component in major food products [16]. In Ayurveda medicine it is used for its rejuvenating properties. It also has a historic place in Chinese medicine. It is used to treat infected wounds; bronchial complaints such as asthma, sinusitis and minor skin inflammations as well as inflammation of the throat, gums and mouth, including mouth ulcers, gingivitis and stomatitis [17].
Materials and Methods
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Chemicals and reagents Theophylline was obtained from BASF, Germany. High performance liquid chromatography (HPLC)-grade acetonitrile and methanol were obtained from Fisher Scientific (Leicestershine, UK) and Panreac Quimica (Barcelona, Espana) respectively. All chemicals used were of the highest available commercial purity. Commiphora myrrha was purchased in dry form from local market. HPLC grade solvents were used for HPLC determinations. All aqueous solutions were prepared using purified water filtered by Milli-QR Gradient A10R (Millipore, Molsheim Cedex, France), having pore size 0.22 μm. All other materials are of analytical grade.
In experimental groups, overnight fasted rabbits (n = 5) were placed in individual restrainer. A polyethylene catheter (BD InsyteTM AutoguardTM Winged, Sandym Utah) was inserted into the ear vein of each rabbit to collect blood samples. Theophylline (16 mg/kg, p. o.) was given orally to each rabbit and blood samples (1.0–1.5 mL) were collected into heparinized vacutainer tubes at 0.0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12, 24 and 36 h. In another group, rabbits were treated with saline suspension of Commiphora myrrha (176 mg/kg, p. o.) for the next 8 consecutive days. The animals were fasted overnight after the 7th day treatment. On the morning of, 8th day, the last dose of Commiphora myrrha was administered to the fasted animals. After 1.0 h of the last dose of Commiphora myrrha, theophylline (16 mg/kg, p. o.) was administered, and the same sampling scheme was repeated as described previously. Each collected samples were centrifuged at 12 000 rpm for 10 min. Plasma was separated and stored at − 80 °C until assayed for theophylline by HPLC method.
Bioanalysis of theophylline The HPLC system consisted of Shimadzu’s CTO-20A Prominence column oven, equipped with SPD 20A UV/VIS detector, SIL-20A Auto sampler, CBM-20A communication Bus Module, LC-20AD solvent delivery pump and DGU-20A5 degasser was used for the assay of theophylline. The data was acquired and processed with Shimadzu LC Solution software. The prontosil C-18 column (5 μm, 150 mm × 4.6 mm i.d) was used. The mobile phase consisted of HPLC water/acetonitrile (92: 8 v/v) with pH of 4.2 adjusted with glacial acetic acid (0.5 mL/L), filtered through a 0.45 μm Millipore filter, and degassed prior to use. The flow rate was 1.0 mL/min. Theophylline was analyzed at a wavelength of 272 nm.
Calibration standards and quality control samples Standard stock solutions of theophylline (2.5 mg/mL) and acetaminophen as IS (1 mg/mL) were prepared in methanol. The solutions were stored in a refrigerator below 8 °C and used for 15 days from the date of preparation. Working solutions of theophylline and IS (100 μg/mL) were prepared in methanol: water (50: 50). Working solutions of theophylline and IS (8 μL) were added to drug-free plasma (200 μL) to obtain final concentrations of 0.25, 0.5, 1.25, 2.5, 5.0, 12.5, and 25.0 μg/mL. The quality control samples at 3 different concentrations were also prepared in a similar manner as the calibration standards. Spiked plasma calibration standards and quality control samples were stored at − 80 ± 2 °C until analyzed.
Sample preparation The protein precipitation method was used to prepare samples for analysis [18]. Plasma samples stored at around − 80 °C were Al-Jenoobi FI et al. Herb-Drug Interaction Study … Drug Res 2015; 65: 312–316
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Study design
314 Original Article
thawed at room temperature and vortex for 30 s to ensure homogeneity. To the 200 μL of plasma sample, 8 μL of methanol, 8 μL of IS (100 μg/mL) and 584 μL of zinc sulphate solution (2 %) was added to precipitate protein of the sample. The samples were again vortex mixed gently for 1.5 min and then centrifuged for 10 min at 12 000 rpm. After centrifugation, 700 μL of clear supernatant was transferred into HPLC vials. The 25 μL of each sample was subjected to HPLC-UV analysis.
total body clearance (CL) as dose/AUC0–∞, mean residence time (MRT) is the ratio of AUMC0–36 and AUC0–36 were calculated.
Statistical analysis Data are presented as the mean ± standard deviation (SD). Differences in pharmacokinetic parameters of theophylline before and after pretreatment with herb were assessed by paired t-test using GraphPad Prism version 3.00 for Windows (San Diego, CA, USA). Statistical significance were assumed when p ≤ 0.05.
Pharmacokinetic analysis
Fig. 2 Plasma concentrations vs. time profile of theophylline following an oral administration in rabbits before and after pretreatment with Commiphora myrrha (mean ± SD).
Table 1 Pharmacokinetic parameters of theophylline following an oral administration in rabbits before and after pretreatment with Commiphora myrrha (n = 5. mean ± SD). Parameters
Control
Theophylline +
p-value
Commiphora
Results
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The comparison of plasma concentration-time profile of the theophylline when given alone to the animal or along with the ▶ Fig. 2. The calibration curves Commiphora myrrha is shown in ● of theophylline prepared in rabbit plasma was found to be linear with respect to the analyte concentration over the range 0.25– 25 μg/mL. The pharmacokinetic parameters, including Cmax, Tmax, ▶ Table 1. AUC0–36, AUC0–∞, AUMC0–36, Ke and t1/2, are given in ● The rate of theophylline absorption which is represented by the parameter (Cmax) after administration of theophylline alone (control) was found to be 25.38 ± 2.25 μg/mL, and Tmax was 3.80 ± 0.45 h, while group treated with theophylline + Commiphora myrrha produced Cmax and Tmax of 17.29 ± 2.45 μg/mL and 3.80 ± 1.30 h respectively. The Cmax was significantly (p = 0.0062) decreased by 31.88 % after treatment the animals with herb as ▶ Table 1). compared with the Cmax of control group (● It was also observed that AUC0–36, AUC0–∞ and AUMC0–36 of control group was 368.28 ± 23.85 μg/mL/h, 394.92 ± 27.50 μg/mL/h and 4 107.51 ± 418.94 μg/mL/h2, however theophylline + Commiphora myrrha treated group presented 214.29 ± 26.78 μg/mL/h, 219.17 ± 26.73 μg/mL/h and 1 997.68 ± 223.10 μg/mL/h2 of AUC0–36, ▶ Table 1) AUC0–∞ and AUMC0–36 respectively (● . Both Cmax and AUC0–∞ were statistically different before and after Commiphora myrrha treatment in rabbits (p < 0.01). The bioavailability of theophylline was decreased (48.63 ± 9.03 %) when drug was co-administered with Commiphora myrrha. The calculated oral clearance increased by 73 % (CL/F from 43.58 ± 2.68 mL h − 1 to 75.66 ± 9.98 mL h − 1; p = 0.0028), while the estimated oral volume of distribution was increased by 31 % (Vd from 536.39 ± 112.69 mL to 705.33 ± 102.48 mL) but this was not sta▶ Table 1). These parameters have resulted tistically significant (● in significant variation in the half-life of theophylline from 10.61 ± 1.41 h to 7.44 ± 0.39 h for control and herb pretreated group respectively in animals, indicates that Commiphora myrrha affects theophylline metabolism to large extent.
myrrha a
Tmax (h) b Cmax (μg/mL) c AUC0→36 h (μgh/mL) d AUC0→∞ (μg/mL/h) e AUMC0 →36 h (μg/mL/h2) f t1/2 (h) g Ke (h − 1) h MRT (h) i CL/F (mL h − 1) j Vd (mL) a
3.80 ± 0.45 25.38 ± 2.25 368.28 ± 23.85 394.92 ± 27.50 4 107.51 ± 418.94 10.61 ± 1.41 0.066 ± 0.008 11.14 ± 0.58 43.58 ± 2.68 536.39 ± 112.69
3.80 ± 1.30 17.29 ± 2.45 214.29 ± 26.78 219.17 ± 26.73 1 997.68 ± 223.10 7.44 ± 0.39 0.093 ± 0.005 9.34 ± 0.25 75.66 ± 9.98 705.33 ± 102.48
0.9999 0.0062 0.0010 0.0007 0.0007 0.0056 0.0007 0.0022 0.0028 0.0573
Time of peak concentration; b Peak of maximum plasma concentration; c Area
under the concentration time profile curve until last observation; d Area under the concentration time profile curve from time 0 to infinity; e Area under the first moment curve until last observation; f Half-life; g Elimination rate constant; h Mean residence time (MRT); i Total clearance; j Volume of distribution
Al-Jenoobi FI et al. Herb-Drug Interaction Study … Drug Res 2015; 65: 312–316
Discussion and Conclusions
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The use of complementary and alternative medicines by asthmatic patients is increasing [19] and most patients consider herbal medicines as safe because they are of natural origin. However, these medicines, which may vary in quality and ingredient content, have the potential to interact with anti-asthmatic drug(s). The interaction of drugs with herbal medicines is a significant safety concern, especially for drugs with narrow therapeutic indices (e. g. theophylline, warfarin and digoxin). Because the pharmacokinetics and/or pharmacodynamics of the drug may be altered by combination with herbal remedies, potentially severe and perhaps even life threatening adverse reactions
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The plasma concentrations were used to construct pharmacokinetic profiles by plotting drug concentration-time curves. To determine the pharmacokinetic parameters, all data were obtained subsequently fed into pharmacokinetic software on Microsoft excel®. The non-compartmental pharmacokinetic parameters such as maximum plasma concentration (Cmax) and time to reach maximum concentration (Tmax), area under the curve from 0 to t (AUC0–36), from 0 to ∞ (AUC0–∞) and area under first moment curve from 0–36 (AUMC0–36), elimination rate constant (Kel) and half-life (t1/2) were calculated. The parameters like volume of distribution (Vd) as (AUMC0–∞/AUC0–∞) × CL and
Original Article 315
mainly metabolized by CYP1A, many CYP1A- metabolized compounds could interact with herb under consideration [29]. Furthermore, our results revealed that Commiphora myrrha could cause decrease in the bioavailability and increase in the elimination rate constant of theophylline per oral. This may pose a negative implication in clinical practice as sub therapeutic concentration of theophylline may easily be reached because of the possibility of decrease in half life and faster drug elimination when theophylline intentionally or unintentionally coadministered with Commiphora myrrha. The significant reduction in AUC as well as decreased in half-life are consistent with an induction of CYP1A enzyme. Based on these results, it was concluded that precaution should be taken to avoid coadministration of Commiphora myrrha with theophylline. Clinical investigations are advised for safe use of Commiphora myrrha with CYP1A substrates.
Acknowledgement
▼
The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group project no. RGP-VPP-268.
Conflict of Interest
▼
All authors have approved the final manuscript and the authors declare that they have no conflicts of interest to disclose.
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may occur [20]. It is important to be aware of the interaction potency of commonly used herbal medicines in order to avoid a reduction in efficacy and an increase in the side-effects of concomitantly administered drugs [6]. The clinical consequence of interactions may be lack of efficacy, toxic reactions, unexpected effects and unforeseen side effects, it is therefore of major importance for patient safety outcomes [21]. Increased blood levels of drugs, related to a decreased activity of the CYP family of enzymes, could result in signs and symptoms of toxicity that are not apparent normally. Conversely, induction of the above enzymes may cause enhanced catabolism, giving rise to subtherapeutic levels and loss of therapeutic control [22]. Overall, interactions between theophylline, a narrow therapeutic index drug and herbal medicines are poorly described in the literature, clearly more research is required. In this regards, the effect of commonly used herbal medicine like Commiphora myrrha on the pharmacokinetic profile of theophylline in rabbits was conducted. The authors believe this is the very first study to report the herb-drug pharmacokinetic interactions between the Commiphora myrrha with drug under consideration. Theophylline is CYP1A substrate and one of the most commonly used anti-asthmatic drug, thus, there is a significant percentage of population who require this drug in their life time. Theophylline is predominantly metabolized by CYP1A, and to a lesser extent by CYP2E and CYP3A [23]. CYP1A is expressed principally in the liver [24]. CYP1A accounts for about 10–15 % of the total CYP content of human liver and metabolizes some important drugs as well as other compounds such as caffeine, and also activates some procarcinogens to carcinogens [25, 26]. CYP1A plays a role in human tobacco-related cancers [27]. Bachmann et al. [28] provided the evidence that theophylline is metabolized principally by CYP1A. In the pretreatment with the CYP1A inducer, β-naphthoflavone, increased theophylline clearance 4.5-fold, and the CYP1A inhibitor, α-naphthoflavone, significantly attenuated the β-naphthoflavone effect. However, the substrates of CYP2E, CYP2D, CYP3A and CYP4A have also been investigated and the result is that it has no significant effect on theophylline clearance. While the powerful CYP3A inducer clotrimazole did not increase theophylline clearance, troleandomycin, an inhibitor of CYP3A, decreased theophylline clearance by about 25 % only. This study has demonstrated that Commiphora myrrha interfere with the theophylline pharmacokinetic to varying degrees in rabbits. In the present study, no overt toxicity was observed with respect to the general behavior of the animals on concurrent administration of either of the herb or theophylline. Herbtreatment for 7 days caused a decrease in Cmax, t1/2, AUC0→∞, Ke and CL/F. This study suggests that simultaneous administration of Commiphora myrrha with theophylline is likely to result in significant interaction. On the basis of pharmacokinetic parameters, significant modulation was observed in the activity of CYP1A. The markedly decreased Cmax and AUC0–t of theophylline caused by coadministration with Commiphora myrrha indicated that the oral bioavailability of theophylline was significantly reduced. The bioavailability of theophylline was found to be decreased about 48.63 % when it was concurrently administered with investigated herb. In addition, there was a 29.88 % decrease in theophylline t1/2 and apparently, the magnitude of theophylline clearance (73.61 %) increased in rabbits. Similarly the ke change quite significantly (p = 0.0007) following the herb administration in rabbits (0.066 h − 1 to 0.093 h − 1). Since theophylline is
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