Eur J Drug Metab Pharmacokinet DOI 10.1007/s13318-014-0199-4
ORIGINAL PAPER
Effects of Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on sildenafil disposition in beagle dogs Abdullah M. Al-Mohizea • Abdul Ahad • Gamal M. El-Maghraby • Fahad I. Al-Jenoobi Khalid M. AlKharfy • Saleh A. Al-Suwayeh
•
Received: 19 September 2013 / Accepted: 1 April 2014 Ó Springer International Publishing Switzerland 2014
Abstract The present study was conducted to investigate the effects of some commonly used herbs namely Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on the pharmacokinetics of sildenafil in beagle dogs. The study design involved four treatments in a non-balanced crossover design. Sildenafil was given one tablet 100 mg orally to each dog and blood samples were obtained. After a suitable washout period, animals were commenced on a specific herb treatment for 1 week. Blood samples were withdrawn at different time intervals and sildenafil was analyzed by HPLC method. Oral administration of Nigella sativa resulted in reduction of AUC0–?, Cmax and t1/2 as compared to the control. Treatment of Lepidium sativum resulted in a significant reduction in the Cmax and AUC. There were no significant differences between the rests of the pharmacokinetic parameters relative to those of the control. For Trigonella foenum-graecum, the effects were similar to those obtained in case of Lepidium sativum. It was concluded that concurrent use of investigated herbs A. M. Al-Mohizea A. Ahad (&) F. I. Al-Jenoobi S. A. Al-Suwayeh Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia e-mail: [email protected]; [email protected] G. M. El-Maghraby Department of Pharmaceutical Technology, College of Pharmacy, University of Tanta, Tanta, Egypt K. M. AlKharfy Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia K. M. AlKharfy Biomarkers Research Program, King Saud University, Riyadh 11451, Saudi Arabia
alters the pharmacokinetics of sildenafil. Co-administration of investigated herbs should be cautious since their concomitant use might result in decrease in sildenafil bioavailability. Keywords Pharmacokinetic Herb–drug interaction Sildenafil Lepidium sativum Nigella sativa Trigonella foenum-graecum
1 Introduction Sildenafil (Fig. 1) is the first oral therapeutic agent for the management of male erectile dysfunction. It is rapidly absorbed after oral administration with peak plasma concentration of about 1 h and half-life of about 4 h. Its plasma protein binding is about 96 % and is primarily eliminated from the body by metabolism with only 15 % of the bioavailable dose excreted unchanged in urine (Wang et al. 2008). It undergoes extensive presystemic elimination after oral administration resulting in low bioavailability. It is eliminated predominantly by hepatic metabolism mainly by cytochrome P450 (CYP) isoenzyme CYP3A and is converted to an active metabolite with properties similar to the parent sildenafil. The metabolite accounts for about 20 % of sildenafil’s pharmacologic effects (Zusman et al. 1999; Hyland et al. 2001). CYP3A is importantly involved in the metabolism of many chemically diverse drugs administered to humans. In addition, its localization in high amounts both in the small intestinal epithelium and liver makes it a major contributor to presystemic elimination following oral drug administration (Thummel and Wilkinson 1998). Sildenafil also has the potential for clinically significant drug interactions with inhibitors of CYP3A because sildenafil is primarily metabolized by CYP3A
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(Gotzkowsky et al. 2013). Several drugs are known to inhibit CYP3A, these include cimetidine (Youlten 2004), ciprofloxacin (McLellan et al. 1996), macrolide antibiotics (Polasek and Miners 2006; Lan et al. 2009) such as erythromycin and clarithromycin, antifungals (Zhang et al. 2012) such as voriconazole, ketoconazole and itraconazole, and protease inhibitors (Ernest et al. 2005) such as saquinavir and ritonavir, etc. In addition, many studies have shown significant herb– drug interactions and many of such interactions were through the modulation of CYP3A. For example, herbal extracts of garlic (Piscitelli et al. 2002), grapefruit juice (Lown et al. 1997), St. John’s Wort (Zhou et al. 2004) and milk thistle (Venkataramanan et al. 2000) modulate the activity of CYP3A resulting in drug interactions. The extracts of certain herbs used in traditional Chinese medicine such as Angelica dahurica (Ishihara et al. 2000), Angelica sinensis (Guo et al. 2001), Ginkgo biloba (Izzo and Ernst 2001), Glycyrrhiza glabra (Budzinski et al. 2000) modulate the CYP3A activity. Herbal remedies are being more commonly used in both healthy individuals and patients suffering from different diseases. It was reported in different studies that the percentages of people using at least one type of alternative medicine were 49 % in France, 48.5 % in Australia, 33 % in USA and 23 % in Denmark. In Saudi Arabia, a similar situation was observed since it was reported that 24 % of patients used at least a type of alternative medicine. Several herbal remedies are widely used in Saudi Arabia (Al-Faris 2000). Some examples of these remedies include seeds of Nigella sativa (black seed) which belongs to the Ranunculaceae family. The seeds are used for many conditions including asthma, diarrhea and dyslipidemia, hypertension, diabetes, inflammation, colic, headache, eczema, fever, and influenza (Kokdil et al. 2006). The active ingredients in the seed include thymoquinone, nigellone, fixed oils (40 %), isoquinoline alkaloid (nigellimine N-oxide) etc. Thymoquinone has been
reported to be an effective antimicrobial and anthelmintic agent. It may also play a role in women’s health, stimulating menstruation and increasing milk flow (Ajayi et al. 2006). However, Trigonella foenum-graecum (Fenugreek) is an annual crop belonging to the Fabaceae family. The important constituents of Trigonella foenum-graecum are simple alkaloids consisting mainly of trigonelline (13 %), choline (0.05 %), gentianine and carpaine, saponine, etc. Medically, fenugreek is reported to have antidiabetic, antifertility, anticancer, antimicrobial, and antiparasitic and hypocholesterolaemic effects (Al-Ajmi 2011). Lepidium sativum (Garden cress) is a fast growing annual herb belonging to the Brassicaceae family. The major constituents of Lepidium sativum seed are glucosinolates (3.5–5.3 %). Other constituents include ascorbic acid (37 %), cucurbitacins, and cardiac steroids (cardenolides). The herb is used for different conditions such as cough, vitamin C deficiency, constipation, poor immunity and as a diuretic. It is useful as poultices for sprains and in leprosy, skin diseases, dysentery and diarrhea (Moser et al. 2009). Since several herbs are traditionally used as food supplements with the aim of increasing the physical fitness and/or the sexual activity. It is thus very likely that these herbs may be taken concurrently with sildenafil. The interactive properties of herbs, which are native to the Saudi Arabian culture, with prescribed medications have not been previously investigated. In particular, there is a lack of information regarding the effects of these herbs on the activity of CYP enzymes. Given the fact that selfmedication is a prevalent practice is Saudi Arabia, more information about possible drug interactions with local herbal products is of a critical importance. Therefore, effects of Lepidium sativum, Nigella sativa, and Trigonella foenum-graecum on the disposition of sildenafil are being explored by this study.
2 Materials and methods 2.1 Materials
Fig. 1 The chemical structure of sildenafil
Viagra tablets (Sildenafil, 100 mg, Pfizer) were used in this study. Sildenafil citrate was obtained from Matrix Laboratories Limited, India. High-performance liquid chromatography (HPLC) grade acetonitrile and methanol were obtained from Fisher Scientific (Leicestershine, UK) and Panreac Quimica (Barcelona, Espana), respectively. Diethyl ether and sodium dihydrogen phosphate were purchased from BDH (Poole, England). All chemicals used were of the highest available commercial purity. All the herbs were purchased in dry form from Saudi market.
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HPLC grade solvents were used for HPLC determinations. All other materials are of analytical grade. 2.2 Animals Healthy male beagle dogs, weighing between 10 and 14 kg, were used as the animal model for pharmacokinetic interaction studies. The animals were obtained after the study was duly approved by the Experimental Animal Care Center, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia (Reference no. C.P.R-153). Animals were maintained in accordance with the recommendations of the ‘Guide for the Care and Use of Laboratory Animals’ approved by the center. The dogs were fasted for about 15 h prior to the experiment, but allowed free access to water. On the morning of the experiment the animals were given 30 g of food (control) or 30 g of food mixed with test herb, 15 min before withdrawing blank blood sample. The tablet was then administered. The dogs were set free in their individual cages throughout the experiment and re-restrained 10 min before sampling time. The legs were shaved and a cephalic vein was cannulated using 18-gauge cannula. The cannula was used for blood sampling. 2.3 Study design and plasma samples The study design involved four treatments in a non-balanced crossover design with a 1 week washout period between each treatment. On the first occasion each dog was given one Viagra tablet (100 mg) after withdrawal of the blank blood. Blood samples (2.5 mL) were collected in evacuated glass tubes (heparinized vacutainers, Becton and Dickinson, CA, USA) before and at 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, and 24.0 h after dosing. The plasma was separated after centrifugation of blood samples for 10 min at 3,000 rpm and stored frozen at -20 °C until analysis. After a washout period of 1 week the dogs were treated with the first herb. The treatment involved oral administration (twice daily) of the herb mixed with 30 g of food for the next eight consecutive days. On the morning of, 8th day, last dose of the herb–food mix was given 15 min before withdrawal of the blank blood sample after which the Viagra tablet was administered and the same sampling scheme was repeated as described previously. The blood samples were stored at -80 °C until analyzed. The same study protocol was followed for each herb. The tested herbs included Lepidium sativum (freshly powdered seeds, given as 7.5 g twice daily), Nigella sativa (freshly powdered seeds, given as 2.5 g twice daily) and Trigonella foenumgraecum (freshly powdered seeds, given as 25 g twice daily) (Alkharfy et al. 2013).
2.4 Sildenafil assay The HPLC (Jasco, Japan) equipped with Jasco PU 2089 quaternary pump, a variable wavelength detector (Jasco plus UV 2077 UV/Vis detector) and an automatic sampling system (Jasco AS 2059 Autosampler) was used for the assay of sildenafil. The BondapakTM (Waters, USA) C-18 column (5 lm, 150 mm 9 4.6 mm i.d) was used. The mobile phase consisted of acetonitrile: Phosphate buffer (20 mM) in the ratio of 35:65 v/v, filtered through a 0.45 lm Millipore filter, and degassed prior to use. The flow rate was 1.0 mL/min, with carbamazepine employed as internal standard. The column effluent was monitored at 240 nm and the chromatographic data analysis was performed with Chrompass software. Each plasma sample (0.5 mL) was added to a clean test tube spiked with the internal standard (500 ng carbamazepine). The tubes were then vortex mixed for 1 min. The samples were then extracted with 4 mL of ether by mechanical shaking for 3 min before centrifugation for 10 min. The ether layer in each tube was transferred to a clean test tube and was evaporated in a water bath at 50 °C. The residue was dissolved in 250 lL of the mobile phase by vortex mixing for 3 min and 30 lL of the resulting solution was injected into the HPLC. Blank plasma was spiked with the internal standard and known amounts of sildenafil to produce standard samples with concentrations in the range of 50–2,000 ng/mL. The concentrations of sildenafil in the unknown samples were determined from the calibration curves. 2.5 Pharmacokinetic analysis A non-compartmental approach was used to analyze sildenafil pharmacokinetic characteristics. To determine pharmacokinetic parameters, all obtained data were subsequently fed into pharmacokinetic software on Microsoft excelÒ. The non-compartmental pharmacokinetic parameters such as maximum plasma sildenafil concentration (Cmax) and time to reach maximum concentration (Tmax), area under the curve from 0 to ? (AUC0–?), elimination rate constant (Kel) and half-life (t1/2) were calculated. The data are presented as mean with standard deviation for the individual groups. 2.6 Statistical analysis Differences in pharmacokinetic parameters of sildenafil before and after treatment with studied herbs were assessed by one-way analysis of variance (ANOVA) followed by Dunnett’s test using GraphPad Prism version 3.00 for Windows (San Diego, CA, USA). Statistical significance was assumed when p B 0.05.
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3 Results and discussion Overall, interactions between sildenafil and herbal medicines are poorly described in the literature, clearly more research is required. In this regards the present pharmacokinetic interaction studies were conducted to investigate the effects of some commonly used herbal medicines such as Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on the pharmacokinetic profile of sildenafil on beagle dogs. The authors believe this is the very first study to report the herb–drug interaction between the sildenafil with herbs under consideration. In this study, the Cmax after administration of sildenafil (control) was found to be 844 ng/mL and the Tmax of 2.38 h was obtained, while group treated with sildenafil ? Nigella sativa produced Cmax and Tmax of 701.8 ng/mL and 1.75 h, respectively. Concurrent administration of sildenafil with Nigella sativa showed decreased in the Tmax of sildenafil compared with that after administration of sildenafil alone, though it was not significantly different (p [ 0.05). It is suggested that the faster absorption of sildenafil might lead to the rapid onset of its clinical effect when sildenafil is co-administered with Nigella sativa. It was also observed that AUC0–? of control group was 7544 ng h/mL, which was significantly (p \ 0.05) higher than AUC0–? (4273 ng h/mL) produced by the sildenafil ? Nigella sativa-treated group as shown in Table 1. The relative bioavailability of sildenafil was decreased (around 43 %) when drug co-administered with Nigella sativa. The comparison of plasma concentration–time profiles of sildenafil when given alone to the beagle dog or along with Nigella sativa is shown in Fig. 2. It was observed that there were no significant Fig. 2 Plasma concentrations versus time profile of sildenafil following an oral administration in beagle dogs before and after pretreatment with tested herbs
Table 1 Pharmacokinetic parameters of sildenafil following an oral administration in beagle dogs before and after pretreatment with Nigella sativa Pharmacokinetic parameter
Treatment Control
a
Cmax (ng/mL)
844 ± 94
Nigella sativa 701.8 ± 99
b
tmax (h)
2.38 ± 0.75
1.75 ± 0.87
c
Kel (h-1)
0.182 ± 0.019
0.235 ± 0.048
d
t1/2 (h)
3.85 ± 0.38
3.06 ± 0.66
e
AUC0–? (ng h/mL)
7544 ± 1340
*4273 ± 1413
n = 5, mean ± SD, *p \ 0.05 a
Peak of maximum plasma concentration
b
Time of peak concentration
c
Elimination rate constant
d
Half-life Area under the concentration time profile curve from time 0 to infinity
e
differences in the t1/2 and Kel of sildenafil between both groups as shown in Table 1. Oral administration of Nigella sativa resulted in reduction of AUC0–?, Cmax, t1/2 and increase in Kel as compared to the control as shown in Table 1. Our results are in agreement with recent study, in which the effect of herbs including Nigella sativa on the disposition of cyclosporine (CYP3A substrate) after oral administration in rabbit model was investigated. The authors claimed that Cmax and AUC0–? were significantly decreased after black seed treatment as compared to controls. There was a significant increase in clearance which leads to a reduction in cyclosporine halflife (Al-Jenoobi et al. 2013a).
Eur J Drug Metab Pharmacokinet Table 2 Pharmacokinetic parameters of sildenafil following an oral administration in beagle dogs before and after pretreatment with Lepidium sativum
Table 3 Pharmacokinetic parameters of sildenafil following an oral administration in beagle dogs before and after pretreatment with Trigonella foenum-graecum
Pharmacokinetic parameter
Pharmacokinetic parameter
Treatment Control
a
Cmax (ng/mL)
844 ± 94
Lepidium sativum
tmax (h)
2.38 ± 0.75
2.25 ± 1.19
c
Kel (h-1)
0.182 ± 0.019
0.177 ± 0.012
3.85 ± 0.38
3.92 ± 0.27
t1/2 (h)
e
AUC0–? (ng h/mL)
7544 ± 1340
Control
**3664 ± 1005
a
844 ± 94
*617 ± 150
b
Cmax (ng/mL) tmax (h)
2.38 ± 0.75
*1.63 ± 0.25
c
Kel (h-1)
0.182 ± 0.019
0.181 ± 0.023
d
t1/2 (h)
3.85 ± 0.38
3.87 ± 0.48
e
AUC0–? (ng h/mL)
7544 ± 1340
**3927 ± 800
n = 5, mean ± SD, * p \ 0.05, ** p \ 0.01 a
Peak of maximum plasma concentration
b
Time of peak concentration
c
Elimination rate constant
Trigonella foenumgraecum
*508.5 ± 238
b
d
Treatment
n = 5, mean ± SD, * p \ 0.05, ** p \ 0.01 a Peak of maximum plasma concentration b
Time of peak concentration
d
c
Elimination rate constant
e
d
Half-life
Half-life Area under the concentration time profile curve from time 0 to infinity
The pharmacokinetic interaction studies of sildenafil ? Lepidium sativum were also conducted on beagle dogs. The comparison of plasma concentration–time profiles and pharmacokinetic parameters of the sildenafil when given alone to the animal or along with Lepidium sativum is shown in Fig. 2 and Table 2. In this case, Tmax of 2.25 h was obtained in sildenafil ? Lepidium sativum-treated group, while control group showed the Tmax of 2.38 h. The rate of sildenafil absorption which is represented by the parameter (Cmax) was significantly (p \ 0.05) decreased when co-administered with Lepidium sativum. The Cmax after administration of sildenafil alone was 844 ng/mL, whereas sildenafil ? Lepidium sativum-treated group produced Cmax of 508.5 ng/mL. It was observed that AUC0–? of control group was 7544 ng h/mL; however, sildenafil ? Lepidium sativum-treated group presented 3664 ng h/mL of AUC0–? as shown in Table 2. The extent of sildenafil absorption represented by the parameter (AUC0–?) was significantly (p \ 0.01) decreased when the drug was taken with Lepidium sativum. The relative bioavailability of sildenafil was found to be decreased (51 %) when drug co-administered with Lepidium sativum. The Kel of sildenafil in Lepidium sativum-treated group was found to be 0.177 (h-1) as shown in Table 2. This effect where there is significant reduction in the extent of absorption as indicated by reduction in the Cmax and AUC0–? with similar elimination rate constant may suggest that the effect of Lepidium sativum could be mainly due to reduction of the drug absorption. Similar results were also reported by Al-Ghazawi et al. (2010), in this study, Pummelo juice reduced the sildenafil Cmax and bioavailability to around
e
Area under the concentration time profile curve from time 0 to infinity
60 % in male healthy volunteers. It was concluded that the faster absorption of sildenafil might lead to the rapid onset of its clinical effect. The comparison of plasma concentration–time profiles and pharmacokinetic parameters of the sildenafil when given alone to the animal or along with Trigonella foenumgraecum is shown in Fig. 2 and Table 3. In pharmacokinetic interaction study of Trigonella foenum-graecum with sildenafil, the Tmax and Cmax of 1.63 h and 617 ng/mL (p \ 0.05) were observed in treated group, which were less than the Tmax and Cmax produced by control group as shown in Table 3. Simultaneous oral administration of Trigonella foenum-graecum contributed to rapid absorption of sildenafil. The AUC0–? of Trigonella foenum-graecumtreated group presented 3927 ng h/mL as shown in Table 3. Co-administration of Trigonella foenum-graecum with sildenafil resulted in 47.95 % decrease in bioavailability of sildenafil as compared to control group. For Trigonella foenum-graecum the effects were similar to those obtained in case of Lepidium sativum. Thus, administration of Trigonella foenum-graecum with sildenafil resulted in a significant reduction in the Cmax and AUC0–? compared to the control as shown in Table 3. There were no significant differences between the values of Kel and t1/2 compared to the control. Our results are in agreement with previous study, in which, both Tmax and AUC0–? of cyclosporine were reduced in comparison to the control group when co-administered with Trigonella foenumgraecum (Al-Jenoobi et al. 2013b).
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4 Conclusion Results obtained from this study suggest that the investigated herbs, Nigella sativa, Lepidium sativum and Trigonella foenum-graecum, have the potential to affect sildenafil absorption as indicated by the significant reduction in their AUC0–? in beagle dogs after co-administration of the herbs (43, 51 and 47.95 %, respectively). Further investigation in human subjects is needed in order to be able to determine the clinical relevance of such interactions. Acknowledgment This study was supported by the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia (Grant number: DSR-AR-2-20). Conflict of interest
The authors report no declarations of interest.
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ORIGINAL PAPER
Effects of Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on sildenafil disposition in beagle dogs Abdullah M. Al-Mohizea • Abdul Ahad • Gamal M. El-Maghraby • Fahad I. Al-Jenoobi Khalid M. AlKharfy • Saleh A. Al-Suwayeh
•
Received: 19 September 2013 / Accepted: 1 April 2014 Ó Springer International Publishing Switzerland 2014
Abstract The present study was conducted to investigate the effects of some commonly used herbs namely Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on the pharmacokinetics of sildenafil in beagle dogs. The study design involved four treatments in a non-balanced crossover design. Sildenafil was given one tablet 100 mg orally to each dog and blood samples were obtained. After a suitable washout period, animals were commenced on a specific herb treatment for 1 week. Blood samples were withdrawn at different time intervals and sildenafil was analyzed by HPLC method. Oral administration of Nigella sativa resulted in reduction of AUC0–?, Cmax and t1/2 as compared to the control. Treatment of Lepidium sativum resulted in a significant reduction in the Cmax and AUC. There were no significant differences between the rests of the pharmacokinetic parameters relative to those of the control. For Trigonella foenum-graecum, the effects were similar to those obtained in case of Lepidium sativum. It was concluded that concurrent use of investigated herbs A. M. Al-Mohizea A. Ahad (&) F. I. Al-Jenoobi S. A. Al-Suwayeh Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia e-mail: [email protected]; [email protected] G. M. El-Maghraby Department of Pharmaceutical Technology, College of Pharmacy, University of Tanta, Tanta, Egypt K. M. AlKharfy Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia K. M. AlKharfy Biomarkers Research Program, King Saud University, Riyadh 11451, Saudi Arabia
alters the pharmacokinetics of sildenafil. Co-administration of investigated herbs should be cautious since their concomitant use might result in decrease in sildenafil bioavailability. Keywords Pharmacokinetic Herb–drug interaction Sildenafil Lepidium sativum Nigella sativa Trigonella foenum-graecum
1 Introduction Sildenafil (Fig. 1) is the first oral therapeutic agent for the management of male erectile dysfunction. It is rapidly absorbed after oral administration with peak plasma concentration of about 1 h and half-life of about 4 h. Its plasma protein binding is about 96 % and is primarily eliminated from the body by metabolism with only 15 % of the bioavailable dose excreted unchanged in urine (Wang et al. 2008). It undergoes extensive presystemic elimination after oral administration resulting in low bioavailability. It is eliminated predominantly by hepatic metabolism mainly by cytochrome P450 (CYP) isoenzyme CYP3A and is converted to an active metabolite with properties similar to the parent sildenafil. The metabolite accounts for about 20 % of sildenafil’s pharmacologic effects (Zusman et al. 1999; Hyland et al. 2001). CYP3A is importantly involved in the metabolism of many chemically diverse drugs administered to humans. In addition, its localization in high amounts both in the small intestinal epithelium and liver makes it a major contributor to presystemic elimination following oral drug administration (Thummel and Wilkinson 1998). Sildenafil also has the potential for clinically significant drug interactions with inhibitors of CYP3A because sildenafil is primarily metabolized by CYP3A
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(Gotzkowsky et al. 2013). Several drugs are known to inhibit CYP3A, these include cimetidine (Youlten 2004), ciprofloxacin (McLellan et al. 1996), macrolide antibiotics (Polasek and Miners 2006; Lan et al. 2009) such as erythromycin and clarithromycin, antifungals (Zhang et al. 2012) such as voriconazole, ketoconazole and itraconazole, and protease inhibitors (Ernest et al. 2005) such as saquinavir and ritonavir, etc. In addition, many studies have shown significant herb– drug interactions and many of such interactions were through the modulation of CYP3A. For example, herbal extracts of garlic (Piscitelli et al. 2002), grapefruit juice (Lown et al. 1997), St. John’s Wort (Zhou et al. 2004) and milk thistle (Venkataramanan et al. 2000) modulate the activity of CYP3A resulting in drug interactions. The extracts of certain herbs used in traditional Chinese medicine such as Angelica dahurica (Ishihara et al. 2000), Angelica sinensis (Guo et al. 2001), Ginkgo biloba (Izzo and Ernst 2001), Glycyrrhiza glabra (Budzinski et al. 2000) modulate the CYP3A activity. Herbal remedies are being more commonly used in both healthy individuals and patients suffering from different diseases. It was reported in different studies that the percentages of people using at least one type of alternative medicine were 49 % in France, 48.5 % in Australia, 33 % in USA and 23 % in Denmark. In Saudi Arabia, a similar situation was observed since it was reported that 24 % of patients used at least a type of alternative medicine. Several herbal remedies are widely used in Saudi Arabia (Al-Faris 2000). Some examples of these remedies include seeds of Nigella sativa (black seed) which belongs to the Ranunculaceae family. The seeds are used for many conditions including asthma, diarrhea and dyslipidemia, hypertension, diabetes, inflammation, colic, headache, eczema, fever, and influenza (Kokdil et al. 2006). The active ingredients in the seed include thymoquinone, nigellone, fixed oils (40 %), isoquinoline alkaloid (nigellimine N-oxide) etc. Thymoquinone has been
reported to be an effective antimicrobial and anthelmintic agent. It may also play a role in women’s health, stimulating menstruation and increasing milk flow (Ajayi et al. 2006). However, Trigonella foenum-graecum (Fenugreek) is an annual crop belonging to the Fabaceae family. The important constituents of Trigonella foenum-graecum are simple alkaloids consisting mainly of trigonelline (13 %), choline (0.05 %), gentianine and carpaine, saponine, etc. Medically, fenugreek is reported to have antidiabetic, antifertility, anticancer, antimicrobial, and antiparasitic and hypocholesterolaemic effects (Al-Ajmi 2011). Lepidium sativum (Garden cress) is a fast growing annual herb belonging to the Brassicaceae family. The major constituents of Lepidium sativum seed are glucosinolates (3.5–5.3 %). Other constituents include ascorbic acid (37 %), cucurbitacins, and cardiac steroids (cardenolides). The herb is used for different conditions such as cough, vitamin C deficiency, constipation, poor immunity and as a diuretic. It is useful as poultices for sprains and in leprosy, skin diseases, dysentery and diarrhea (Moser et al. 2009). Since several herbs are traditionally used as food supplements with the aim of increasing the physical fitness and/or the sexual activity. It is thus very likely that these herbs may be taken concurrently with sildenafil. The interactive properties of herbs, which are native to the Saudi Arabian culture, with prescribed medications have not been previously investigated. In particular, there is a lack of information regarding the effects of these herbs on the activity of CYP enzymes. Given the fact that selfmedication is a prevalent practice is Saudi Arabia, more information about possible drug interactions with local herbal products is of a critical importance. Therefore, effects of Lepidium sativum, Nigella sativa, and Trigonella foenum-graecum on the disposition of sildenafil are being explored by this study.
2 Materials and methods 2.1 Materials
Fig. 1 The chemical structure of sildenafil
Viagra tablets (Sildenafil, 100 mg, Pfizer) were used in this study. Sildenafil citrate was obtained from Matrix Laboratories Limited, India. High-performance liquid chromatography (HPLC) grade acetonitrile and methanol were obtained from Fisher Scientific (Leicestershine, UK) and Panreac Quimica (Barcelona, Espana), respectively. Diethyl ether and sodium dihydrogen phosphate were purchased from BDH (Poole, England). All chemicals used were of the highest available commercial purity. All the herbs were purchased in dry form from Saudi market.
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HPLC grade solvents were used for HPLC determinations. All other materials are of analytical grade. 2.2 Animals Healthy male beagle dogs, weighing between 10 and 14 kg, were used as the animal model for pharmacokinetic interaction studies. The animals were obtained after the study was duly approved by the Experimental Animal Care Center, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia (Reference no. C.P.R-153). Animals were maintained in accordance with the recommendations of the ‘Guide for the Care and Use of Laboratory Animals’ approved by the center. The dogs were fasted for about 15 h prior to the experiment, but allowed free access to water. On the morning of the experiment the animals were given 30 g of food (control) or 30 g of food mixed with test herb, 15 min before withdrawing blank blood sample. The tablet was then administered. The dogs were set free in their individual cages throughout the experiment and re-restrained 10 min before sampling time. The legs were shaved and a cephalic vein was cannulated using 18-gauge cannula. The cannula was used for blood sampling. 2.3 Study design and plasma samples The study design involved four treatments in a non-balanced crossover design with a 1 week washout period between each treatment. On the first occasion each dog was given one Viagra tablet (100 mg) after withdrawal of the blank blood. Blood samples (2.5 mL) were collected in evacuated glass tubes (heparinized vacutainers, Becton and Dickinson, CA, USA) before and at 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, and 24.0 h after dosing. The plasma was separated after centrifugation of blood samples for 10 min at 3,000 rpm and stored frozen at -20 °C until analysis. After a washout period of 1 week the dogs were treated with the first herb. The treatment involved oral administration (twice daily) of the herb mixed with 30 g of food for the next eight consecutive days. On the morning of, 8th day, last dose of the herb–food mix was given 15 min before withdrawal of the blank blood sample after which the Viagra tablet was administered and the same sampling scheme was repeated as described previously. The blood samples were stored at -80 °C until analyzed. The same study protocol was followed for each herb. The tested herbs included Lepidium sativum (freshly powdered seeds, given as 7.5 g twice daily), Nigella sativa (freshly powdered seeds, given as 2.5 g twice daily) and Trigonella foenumgraecum (freshly powdered seeds, given as 25 g twice daily) (Alkharfy et al. 2013).
2.4 Sildenafil assay The HPLC (Jasco, Japan) equipped with Jasco PU 2089 quaternary pump, a variable wavelength detector (Jasco plus UV 2077 UV/Vis detector) and an automatic sampling system (Jasco AS 2059 Autosampler) was used for the assay of sildenafil. The BondapakTM (Waters, USA) C-18 column (5 lm, 150 mm 9 4.6 mm i.d) was used. The mobile phase consisted of acetonitrile: Phosphate buffer (20 mM) in the ratio of 35:65 v/v, filtered through a 0.45 lm Millipore filter, and degassed prior to use. The flow rate was 1.0 mL/min, with carbamazepine employed as internal standard. The column effluent was monitored at 240 nm and the chromatographic data analysis was performed with Chrompass software. Each plasma sample (0.5 mL) was added to a clean test tube spiked with the internal standard (500 ng carbamazepine). The tubes were then vortex mixed for 1 min. The samples were then extracted with 4 mL of ether by mechanical shaking for 3 min before centrifugation for 10 min. The ether layer in each tube was transferred to a clean test tube and was evaporated in a water bath at 50 °C. The residue was dissolved in 250 lL of the mobile phase by vortex mixing for 3 min and 30 lL of the resulting solution was injected into the HPLC. Blank plasma was spiked with the internal standard and known amounts of sildenafil to produce standard samples with concentrations in the range of 50–2,000 ng/mL. The concentrations of sildenafil in the unknown samples were determined from the calibration curves. 2.5 Pharmacokinetic analysis A non-compartmental approach was used to analyze sildenafil pharmacokinetic characteristics. To determine pharmacokinetic parameters, all obtained data were subsequently fed into pharmacokinetic software on Microsoft excelÒ. The non-compartmental pharmacokinetic parameters such as maximum plasma sildenafil concentration (Cmax) and time to reach maximum concentration (Tmax), area under the curve from 0 to ? (AUC0–?), elimination rate constant (Kel) and half-life (t1/2) were calculated. The data are presented as mean with standard deviation for the individual groups. 2.6 Statistical analysis Differences in pharmacokinetic parameters of sildenafil before and after treatment with studied herbs were assessed by one-way analysis of variance (ANOVA) followed by Dunnett’s test using GraphPad Prism version 3.00 for Windows (San Diego, CA, USA). Statistical significance was assumed when p B 0.05.
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3 Results and discussion Overall, interactions between sildenafil and herbal medicines are poorly described in the literature, clearly more research is required. In this regards the present pharmacokinetic interaction studies were conducted to investigate the effects of some commonly used herbal medicines such as Nigella sativa, Lepidium sativum and Trigonella foenum-graecum on the pharmacokinetic profile of sildenafil on beagle dogs. The authors believe this is the very first study to report the herb–drug interaction between the sildenafil with herbs under consideration. In this study, the Cmax after administration of sildenafil (control) was found to be 844 ng/mL and the Tmax of 2.38 h was obtained, while group treated with sildenafil ? Nigella sativa produced Cmax and Tmax of 701.8 ng/mL and 1.75 h, respectively. Concurrent administration of sildenafil with Nigella sativa showed decreased in the Tmax of sildenafil compared with that after administration of sildenafil alone, though it was not significantly different (p [ 0.05). It is suggested that the faster absorption of sildenafil might lead to the rapid onset of its clinical effect when sildenafil is co-administered with Nigella sativa. It was also observed that AUC0–? of control group was 7544 ng h/mL, which was significantly (p \ 0.05) higher than AUC0–? (4273 ng h/mL) produced by the sildenafil ? Nigella sativa-treated group as shown in Table 1. The relative bioavailability of sildenafil was decreased (around 43 %) when drug co-administered with Nigella sativa. The comparison of plasma concentration–time profiles of sildenafil when given alone to the beagle dog or along with Nigella sativa is shown in Fig. 2. It was observed that there were no significant Fig. 2 Plasma concentrations versus time profile of sildenafil following an oral administration in beagle dogs before and after pretreatment with tested herbs
Table 1 Pharmacokinetic parameters of sildenafil following an oral administration in beagle dogs before and after pretreatment with Nigella sativa Pharmacokinetic parameter
Treatment Control
a
Cmax (ng/mL)
844 ± 94
Nigella sativa 701.8 ± 99
b
tmax (h)
2.38 ± 0.75
1.75 ± 0.87
c
Kel (h-1)
0.182 ± 0.019
0.235 ± 0.048
d
t1/2 (h)
3.85 ± 0.38
3.06 ± 0.66
e
AUC0–? (ng h/mL)
7544 ± 1340
*4273 ± 1413
n = 5, mean ± SD, *p \ 0.05 a
Peak of maximum plasma concentration
b
Time of peak concentration
c
Elimination rate constant
d
Half-life Area under the concentration time profile curve from time 0 to infinity
e
differences in the t1/2 and Kel of sildenafil between both groups as shown in Table 1. Oral administration of Nigella sativa resulted in reduction of AUC0–?, Cmax, t1/2 and increase in Kel as compared to the control as shown in Table 1. Our results are in agreement with recent study, in which the effect of herbs including Nigella sativa on the disposition of cyclosporine (CYP3A substrate) after oral administration in rabbit model was investigated. The authors claimed that Cmax and AUC0–? were significantly decreased after black seed treatment as compared to controls. There was a significant increase in clearance which leads to a reduction in cyclosporine halflife (Al-Jenoobi et al. 2013a).
Eur J Drug Metab Pharmacokinet Table 2 Pharmacokinetic parameters of sildenafil following an oral administration in beagle dogs before and after pretreatment with Lepidium sativum
Table 3 Pharmacokinetic parameters of sildenafil following an oral administration in beagle dogs before and after pretreatment with Trigonella foenum-graecum
Pharmacokinetic parameter
Pharmacokinetic parameter
Treatment Control
a
Cmax (ng/mL)
844 ± 94
Lepidium sativum
tmax (h)
2.38 ± 0.75
2.25 ± 1.19
c
Kel (h-1)
0.182 ± 0.019
0.177 ± 0.012
3.85 ± 0.38
3.92 ± 0.27
t1/2 (h)
e
AUC0–? (ng h/mL)
7544 ± 1340
Control
**3664 ± 1005
a
844 ± 94
*617 ± 150
b
Cmax (ng/mL) tmax (h)
2.38 ± 0.75
*1.63 ± 0.25
c
Kel (h-1)
0.182 ± 0.019
0.181 ± 0.023
d
t1/2 (h)
3.85 ± 0.38
3.87 ± 0.48
e
AUC0–? (ng h/mL)
7544 ± 1340
**3927 ± 800
n = 5, mean ± SD, * p \ 0.05, ** p \ 0.01 a
Peak of maximum plasma concentration
b
Time of peak concentration
c
Elimination rate constant
Trigonella foenumgraecum
*508.5 ± 238
b
d
Treatment
n = 5, mean ± SD, * p \ 0.05, ** p \ 0.01 a Peak of maximum plasma concentration b
Time of peak concentration
d
c
Elimination rate constant
e
d
Half-life
Half-life Area under the concentration time profile curve from time 0 to infinity
The pharmacokinetic interaction studies of sildenafil ? Lepidium sativum were also conducted on beagle dogs. The comparison of plasma concentration–time profiles and pharmacokinetic parameters of the sildenafil when given alone to the animal or along with Lepidium sativum is shown in Fig. 2 and Table 2. In this case, Tmax of 2.25 h was obtained in sildenafil ? Lepidium sativum-treated group, while control group showed the Tmax of 2.38 h. The rate of sildenafil absorption which is represented by the parameter (Cmax) was significantly (p \ 0.05) decreased when co-administered with Lepidium sativum. The Cmax after administration of sildenafil alone was 844 ng/mL, whereas sildenafil ? Lepidium sativum-treated group produced Cmax of 508.5 ng/mL. It was observed that AUC0–? of control group was 7544 ng h/mL; however, sildenafil ? Lepidium sativum-treated group presented 3664 ng h/mL of AUC0–? as shown in Table 2. The extent of sildenafil absorption represented by the parameter (AUC0–?) was significantly (p \ 0.01) decreased when the drug was taken with Lepidium sativum. The relative bioavailability of sildenafil was found to be decreased (51 %) when drug co-administered with Lepidium sativum. The Kel of sildenafil in Lepidium sativum-treated group was found to be 0.177 (h-1) as shown in Table 2. This effect where there is significant reduction in the extent of absorption as indicated by reduction in the Cmax and AUC0–? with similar elimination rate constant may suggest that the effect of Lepidium sativum could be mainly due to reduction of the drug absorption. Similar results were also reported by Al-Ghazawi et al. (2010), in this study, Pummelo juice reduced the sildenafil Cmax and bioavailability to around
e
Area under the concentration time profile curve from time 0 to infinity
60 % in male healthy volunteers. It was concluded that the faster absorption of sildenafil might lead to the rapid onset of its clinical effect. The comparison of plasma concentration–time profiles and pharmacokinetic parameters of the sildenafil when given alone to the animal or along with Trigonella foenumgraecum is shown in Fig. 2 and Table 3. In pharmacokinetic interaction study of Trigonella foenum-graecum with sildenafil, the Tmax and Cmax of 1.63 h and 617 ng/mL (p \ 0.05) were observed in treated group, which were less than the Tmax and Cmax produced by control group as shown in Table 3. Simultaneous oral administration of Trigonella foenum-graecum contributed to rapid absorption of sildenafil. The AUC0–? of Trigonella foenum-graecumtreated group presented 3927 ng h/mL as shown in Table 3. Co-administration of Trigonella foenum-graecum with sildenafil resulted in 47.95 % decrease in bioavailability of sildenafil as compared to control group. For Trigonella foenum-graecum the effects were similar to those obtained in case of Lepidium sativum. Thus, administration of Trigonella foenum-graecum with sildenafil resulted in a significant reduction in the Cmax and AUC0–? compared to the control as shown in Table 3. There were no significant differences between the values of Kel and t1/2 compared to the control. Our results are in agreement with previous study, in which, both Tmax and AUC0–? of cyclosporine were reduced in comparison to the control group when co-administered with Trigonella foenumgraecum (Al-Jenoobi et al. 2013b).
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4 Conclusion Results obtained from this study suggest that the investigated herbs, Nigella sativa, Lepidium sativum and Trigonella foenum-graecum, have the potential to affect sildenafil absorption as indicated by the significant reduction in their AUC0–? in beagle dogs after co-administration of the herbs (43, 51 and 47.95 %, respectively). Further investigation in human subjects is needed in order to be able to determine the clinical relevance of such interactions. Acknowledgment This study was supported by the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia (Grant number: DSR-AR-2-20). Conflict of interest
The authors report no declarations of interest.
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