2 Department of Medical Management, Chodang University, Jeollanam-do 58530, Republic of Korea
Recently, the interest in fruits or vegetables as an alternative medicine has been growing . Thus, there are increasing studies to identify plant-based natural compounds that regulate P-gp and metabolic enzymes. Nevertheless, the pharmacokinetic interactions between fruit or vegetable constituents and drugs were not well studied. Therefore, preclinical and clinical studies are required for the interaction between the fruit or vegetable ingredients and the drugs.
Kaempferol (3, 5, 7-trihydroxy-2-(4-hydroxyphenyl)-4H- 1-benzopyran-4-one) is a flavonoid, that abundantly found in onions (832 mg·kg-1), carrots (140 mg·kg-1), and black (118 mg·kg-1) . In the small intestine, P-gp is located on the apical membrane of the cell with CYP3A4 [3-4]. P-gp and CYP3A4 can synergize to limit oral absorption and first-pass metabolism . Kaempferol was reported as a substrate for P-gp .
Nifedipine is extensively used for the clinical treatment of vascular diseases included hypertension, coronary artery spasm, and angina pectoris in classification of calcium channel-blocker . Nifedipine physically blocks channels to inhibit extracellular calcium influx through myocardial and vascular membranes, reduce intracellular calcium levels, inhibit smooth muscle cells contraction, and dilate the coronary and systemic arteries .
Nifedipine is mainly metabolized by cytochrome P450 (CYP) 3A4, a major pyridine metabolite, dehydronifedipine . CYP enzymes play a main role in the phase I metabolism of the drug and are responsible for the oxidation metabolism of many xenobiotics . CYP3A3 is located in the liver and metabolizes more than 50% of the drugs including nifedipine and erythromycin [10-11]. Nifedipine is known to be a substrate for CYP3A4 in humans .
P-gp is a member of the adenosine triphosphate (ATP) dependent transmembrane efflux pump. P-gp has been observed in the gastrointestinal epithelium, canalicular membrane of the liver and kidney in normal tissues [12-13].
P-gp plays a pharmacokinetic role because it belongs to various tissues and has substrate [14-15]. The substrates and/or inhibitors of CYP3A4 and P-gp were known to overlap each other overlap with each other . In previous studies, kaempferol exhibited a remarkable inhibition of the P-gp-mediated efflux of ritonavir, thereby increasing its cellular uptake . Thus, kaempferol would be expected to alter the pharmacokinetics of nifedipine by inhibiting P-gp and CYP3A4 in rats.
Therefore, the aim of this study was to evaluate the CYP3A4 and P-gp activity on the effects of kaempferol. In addition, we evaluated the bioavailability and pharmacokinetics of orally and intravenously administered nifedipine in rats with or without kaempferolMaterial and Methods Materials
Nifedipine, dehydronifedipine, kaempferol and amlodipine [internal standard for the high-performance liquid chromatography (HPLC) analysis of nifedipine] were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). Methanol, isooctane, methyl-tert-butyl ether (MTBE), analytical grade acetic acid and triethylamine (TEA) were obtained from Merck Co. (Darmstadt, Germany). Rhodamine was obtained from Calbiochem (San Diego, CA, USA), and the CYP inhibition assay kit was obtained from Gentest Co. (Woburn, MA, USA). Other chemicals used were of reagent or HPLC grade. The apparatus used in this study included an HPLC system equipped with a Waters 1515 isocratic HPLC pump, a Waters 717 plus autosampler, a WatersTM 2487 scanning UV detector (Waters Co., Milford, MA, USA), an HPLC column temperature controller (Phenomenex Inc., CA, USA), a Bransonic® Ultrasonic Cleaner (Branson Ultrasonic Co., Danbury, CT, USA), a vortexmixer (Scientific Industries Co., NY, USA), and a high-speed microcentrifuge (Hitachi Co., Tokyo, Japan).Animal
All animal study protocols were approved by the Animal Care Committee of Chosun University (Gwangju, Republic of Korea). The experiment was carried out in accordance with the guidelines of the National Institutes of Health (NIH publication No. 8623, revised 1985). Male Sprague-Dawley rats (250-280 g) were purchased from the Dae Han Laboratory Animal Research Co. (Eumsung, Republic of Korea). Animals were allowed free access to a normal standard chow diet (No. 322-7-1; Superfeed Co., Wonju, Republic of Korea) and tap water. The animals were housed, four or five per cage, in laminar flow cages maintained at a temperature of 22 ± 2 ℃, 50%-60% relative humidity, and under a 12 h light-dark cycle. The rats were adapted for at least a week under these conditions.
The rats were fasted for at least 24 h prior to the experiments. The left femoral artery (for blood sampling) and left femoral vein (for drug administration in the intravenous study) were cannulated using an SP45 polyethylene tube (inner diameter, 0.58 mm, outer diameter, 0.96 mm; Natsume Seisakusho Company, Tokyo, Japan) while each rat was under CO2 gas anesthesia.Intravenous and oral administration of nifedipine
The rats were divided into six groups (n = 6, in each) as follows: oral groups administered [10 mg·kg-1 of nifedipine dissolved in distilled water emulsified with 10 µL tween 80 (1.0 mL·kg-1)] without (control) or with 0.4, 2.0 or 10 mg·kg-1 of kaempferol (emulsified with 10 µL tween 80; total oral volume of 1.0 mL·kg-1), and intravenous groups administered (2.5 mg·kg-1 of nifedipine in 0.9% NaCl-injectable solution; emulsified with 10 µL tween 80, 1.0 mL·kg-1) without (control) or with 0.4, 2.0 or 10 mg·kg-1 of kaempferol (emulsified with 10 µL tween 80). A feeding tube was used to administer nifedipine and kaempferol intragastrically. Kaempferol was administered 30 min prior to oral administration of nifedipine. Blood samples (0.5 mL) were collected in heparinized tubes via the femoral artery at 0.017 (end of drug infusion), 0.1, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h for the intravenous study, and 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, and 24 h for the oral study. Whole blood (approximately 1.2 mL) collected from untreated rats was infused via the femoral artery at 0.75, 4, and 8 h to replace blood loss from blood sampling. The blood samples were centrifuged (13 000 r·min-1, 3 min), and 200-µL aliquots of plasma samples were stored in the deep freezer at -40 ℃ until the HPLC analysis.HPLC analysis
The plasma concentrations of nifedipine in rats were determined using an HPLC assay with some modified the previous report . Briefly, 50 µL of amlodipine (3 µg·mL-1), as the internal standard and 50 µL of 1.0 mol·L-1 sodium hydroxide were added to 0.2 mL of the plasma samples and mixed for 3 s and 5 mL of MTBE-isooctane (75 : 25, V/V) was added. The resultant mixture was vortex-mixed for 1 min and centrifuged at 3000 r·min-1 for 5 min. The organic layer (0.8 mL) was transferred into a clean test tube and evaporated under a gentle stream of nitrogen gas at room condition. The dried extracts were reconstituted with 200 µL of the mobile phase vortex-mixed for 1 min. The aliquots of 160 µL were transferred to a clean HPLC vials. The supernatant (70 µL) was injected into the HPLC system. The UV detector wavelength was set to 350 nm, and a Nova-pack C8 column (100 mm × 8 mm I.D., 4 µm; Waters Co., Milford, MA, USA) was used at room temperature. A mixture of methanol and water (62 : 38, V/V, pH 4.5, adjusted with acetic acid, 320 µL TEA/1000 mL of mixture was added) was used as the mobile phase with a flow rate of 1.0 mL·min-1. The retention times were as follows: 16.8 min for internal standard, 8.2 min for nifedipine, and 6.5 min for dehydronifedipine. The detection limits of nifedipine and dehydronifedipine in rat plasma were all 5 ng·mL-1. The coefficients of variation for nifedipine and dehydronifedipine were all below 5.0%.CYP3A4 inhibition assay
This experiment was performed to study the inhibitory effect of kaempferol on CYP3A4 activity, as nifedipine and kaempferol are both substrates of CYP3A4. The inhibition assay for the human CYP3A4 enzyme activity was performed using a CYP inhibition assay kit (GENTEST, Woburn, MA) as described previously . Briefly, human CYP enzyme was obtained from baculovirus-infected insect cells. The CYP substrate (7-BFC for CYP3A4) was incubated with or without the test compounds in the enzyme/substrate buffer with 1 pmol of P450 enzyme and an NADPH-generating system (1.3 mmol·L-1 NADP, 3.54 mmol·L-1 glucose 6-phosphate, 0.4 U·mL-1 glucose 6-phosphate dehydrogenase and 3.3 mmol·L-1 MgCl2) in potassium phosphate buffer (pH 7.4). After 45 min, reactions were terminated by adding the stop solution. Metabolite concentrations of samples were measured with a spectrofluorometer (Molecular Device, Sunnyvale, CA, USA) at an excitation wavelength of 409 nm and an emission wavelength of 530 nm. The positive control (1 µmol·L-1 ketoconazole for CYP3A4) was run on the same plate and showed 99% inhibition. All experiments were done in duplicate, and the results were expressed as percentage inhibition.Rhodamine-123 retention assay
This study was conducted to investigate the effect of kaempferol on P-gp since kaempferol is a substrate for P-gp. The procedures used for the Rhodamine-123 retention assay were similar to previously reported methods . The MCF-7/ADR cells were seeded 3 × 105 in 24-well plates. At 80% confluence, the cells were incubated in fetal bovine serum (FBS)-free Dulbecco's modified Eagle's medium (DMEM) for 18 h. The culture medium was changed to Hanks' balanced salt solution (HBSS) and the cells were incubated at 37 °C for 30 min. Following incubation of the cells with 20 µmol·L-1 rhodamine-123 in the presence or absence of kaempferol (0, 50 and 100 µmol·L-1) and verapamil (positive control, 100 µmol·L-1) for 90 min, the medium was completely removed. The cells were then washed three times with ice-cold phosphate buffer (pH 7.0) and lysed in EBC lysis buffer. Rhodamine-123 fluorescence in the cell lysates was measured using excitation and emission wavelengths of 480 and 540 nm, respectively. Fluorescence values were normalized to the total protein content of each sample and were presented as a ratio to the control.Pharmacokinetic analysis
The plasma concentration data were analyzed by the non-compartmental method using the Thermo Kinetica Software Version 5.0 (Thermo Fisher Scientific Inc., Miami, OK, USA). The parameter values were obtained by fitting the data to the pharmacokinetic model using the simplex algorithm. The area under the plasma concentration-time curve (AUC0-∞) was calculated by the trapezoidal rule-extrapolation method . The peak concentration (Cmax) of nifedipine in plasma and the time to reach Cmax (Tmax) were obtained by visual inspection of the data from the concentration-time curve. The terminal half-life (t1/2) was calculated by 0.693/Kel. The total body clearance (CL/F) was calculated by dose/AUC. The absolute bioavailability (AB) was calculated by AUCoral/AUCi.v. × dosei.v./doseoral, and the relative bioavailability (RB) of nifedipine were calculated by AUCnifedipine with kaempferol/ AUCcontrol. The metabolite-parent AUC ratio (MR) was calculated by AUCdehydronifedipine/AUCnifedipine.Statistical analysis
The data are presented as the mean ± standard deviation (SD). The pharmacokinetic parameters were compared using a one-way analysis of variance (ANOVA), followed by a posteriori testing with the use of the Dunnett correction. A P value of < 0.05 was considered statistically significant.Results Effect of kaempferol on CYP3A4 activity
The inhibitory effect of kaempferol on CYP3A4 activity was shown in Fig. 1. The positive control as ketoconazole inhibited CYP3A4 activity with IC50 value of 0.14 µmol·L-1. Kaempferol inhibited CYP3A4 activity depended on concentration manner with an IC50 value of 8.6 µmol·L-1. Although the IC50 of kaempferol was lower than that of ketoconazole, the inhibitory effect of CYP3A4 in kaempferol was confirmed.
The accumulation of rhodamine-123, a P-gp substrate, was increased in MCF-7/ADR cells overexpressing P-gp compared to the accumulation observed in MCF-7 cells lacking P-gp, as shown in Fig. 2. The concurrent use of kaempferol (P < 0.05 for 100 µmol·L-1) enhanced the cellular uptake of rhodamine-123 in a concentration-dependent manner. This result suggests that kaempferol significantly inhibited P-gp activity.
The mean plasma concentration-time profiles of nifedipine in the presence and absence of kaempferol (0.4, 2.0 and 10 mg·kg-1) are shown in Fig 3. The pharmacokinetic parameters of nifedipine are summarized in Table 1. Kaempferol significantly (2.0 mg·kg-1, P < 0.05; 10.0 mg·kg-1, P < 0.01) increased the AUC0-∞ of nifedipine and the Cmax of nifedipine by 38.1%-55.7% and 19.6%-52.4% respectively. The CL/F was significantly decreased (26.0%-35.6%) by kaempferol at doses of 2.0 mg·kg-1 (P < 0.05) and 10.0 mg·kg-1 (P < 0.01). The AB values of nifedipine in the presence of kaempferol (2.0, or 10 mg·kg-1) were significantly higher (34.8%-55.7%, P < 0.05; P < 0.01) than those in the control group. Kaempferol increased the RB of nifedipine 1.38-1.56 fold. In summary, The AUC0-∞, AB values, and RB values were significantly increased depended on kaempferol concentration manners compared to those of the control group.
The plasma concentration-time profiles of dehydronifedipine are shown in Fig 4. The pharmacokinetic parameters of dehydronifedipine are summarized in Table 2. Kaempferol increased the AUC0-∞ of dehydronifedipine, but this was not significant. The MR ratios were significantly (P < 0.05) decreased by kaempferol at doses of 2 and 10 mg·kg-1 by 19.5% and 25.0%, respectively. This result suggests that the formation of dehydronifedipine was considerably altered by kaempferol. The increase in the bioavailability of nifedipine may be mainly because of the inhibition of CYP3A4 activity by kaempferol in the small intestine or liver or both.
The mean arterial plasma concentration-time profiles of nifedipine following its intravenous administration of nifedipine (2.5 mg·kg-1) in rats in the presence or absence of kaempferol (0.4, 2.0 and 10.0 mg·kg-1) are shown in Fig. 5, and the corresponding pharmacokinetic parameters are shown in Table 3. Kaempferol (2.0 and 10 mg·kg-1) significantly (P < 0.05) increased the AUC0-∞ of nifedipine by 23.0%- 30.1%. The CLt was significantly decreased (19.3%-25.6%, P < 0.05) by kaempferol at doses of 2.0 and 10 mg·kg-1. The t1/2 of nifedipine was also increased, but this increase was not statistically significant.
In recent years, dependence on pharmaceuticals has been gradually decreasing, and patients were looking for alternative medicines with lower drug efficacy but fewer side effects and easier to purchase. With the growing great interest in fruit or vegetable components as alternative medicine, effort is currently being put into identifying plant-based natural compounds that modulate P-gp and metabolic enzymes. However, there is very little information on the pharmacokinetic interactions between fruit or vegetable components and drugs. More preclinical and clinical investigations of the possible interactions between fruit or vegetable constituents and drugs are needed. Such studies would contribute to preventing potential adverse reactions in patients. Alternatively, this information may also be useful because the identified interactions may prove to possess potentially beneficial therapeutic applications. Therefore, the present study evaluated the effect of kaempferol (a main component of onion) on the bioavailability and pharmacokinetics of nifedipine in rats. We investigated whether the potential interactions between our hypothesized kaempferol and nifedipine could be mediated through dual inhibition of CYP3A4 and P-gp. Furthermore, since kaempferol or onion juice is readily available over-the- counter, there is a possibility that kaempferol or onion juice as a health supplement may be taken along with prescribing nifedipine for the treatment of cardiovascular disease.
In Fig. 1, kaempferol (IC50 value of 8.6 µmol·L-1) has a lower inhibitory effect on CYP3A4 than ketoconazole (IC50 value of 0.14 µmol·L-1). When inhibitory effect on CYP3A4 activity (< 15 µmol·L-1 in IC50), the bioavailability (AUC) of CYP3A4 substrates was increased by only CYP3A4 inhibitors [22-24]. Our results were similar to those of a previous paper . Moreover, the pharmacokinetic parameters of nifedipine were evaluated in rats in the absence and presence of kaempferol. Human CYP2C9 and 3A4 and rat CYP2C11 and 3A4 have 77% and 73% protein homology, respectively [22, 24, 26]. In particular, CYP3A4 expressed in rats corresponds to the function of CYP3A4 in humans [22-24, 27-28].
In Fig. 2, the concentration of kaempferol (100 µmol·L-1) was significantly (P < 0.05) inhibited P-gp activity. Our results for P-gp inhibition were similar to that of a previous paper . In general, P-gp affects the absorption of drugs by efflux transport. The inhibition of P-gp activity was performed generally to compare with verapamil 100 µmol·L-1 standard index of inhibition [23-24]. Therefore, concomitant administration of kaempferol may affect the bioavailability and pharmacokinetics of orally administered nifedipine. Nifedipine for oral administration was a substrate for both CYP3A4-mediated metabolism and P-gp-mediated efflux in the intestine and liver.
In Table 1, kaempferol significantly increased AUC0-∞ and Cmax of nifedipine. Depending on increased kaempferol, AUC0-∞ and Cmax of nifedipine were increased to 56% and 52%, respectively. The AB of nifedipine in the presence of kaempferol was significantly higher than that of control group. However, the CL/F of nifedipine was significantly decreased by kaempferol. In previous studies, grapefluit, oral diallyl trisulfide (major organosulfur compounds derived from garlic), resveratrol and quercetin significantly increased the bioavailability of losartan, nifedipine, nicardipine and tamoxifen by inhibiting CYP3A4 in rats [22, 27-28, 30]. The results of our study are almost similar to those of the above paper.
Moreover, the absolute bioavailability (AB) of nifedipine was reported to be 53% in human after oral administration . As a result of our study, the AB value of nifedipine was 15.8%, indicating a difference between human and rat data. Combined administration of kaempferol increased the AB value of nifedipine by 55% and could be expected to be 53% to 80% in humans.
As summarized in Table 2, kaempferol significantly decreased metabolite-parent AUC ratios (MR). Therefore, a decrease of the MR of nifedipine in present study may be mainly due to the inhibitory effect of kaempferol on the metabolic first-pass effects in the liver or small intestine. In a previous study, myricetin significantly increased AUCs of losartan and decreased the MR of losartan in rats . Therefore, our results were similar to those of the previous study.
Kaempferol significantly altered the pharmacokinetic parameters of intravenously administered nifedipine in Table 3. Kaempferol significantly increased the AUC0-∞ of nifedipine. However, this result is not consistent with previous studies, showing that hesperidine did not increase the AUCs of intravenous verapamil in rats [22-32]. In summary, kaempferol inhibited CYP3A4 enzyme activity and enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Moreover, the relative bioavailability (RB) of nifedipine in the presence of kaempferol was significantly higher than those of the control group after oral and intravenous administration. The metabolite of parent drug AUC ratio (MR) in the presence of kaempferol was signifycantly decreased compared to that of control group. Therefore, this study, which increased relative bioavailability of nifedipine in the presence of kaempferol and reduces metabolite of parent drug AUC ratio (MR), will be an important basis for drug-drug interactions. Furthermore, since kaempferol (a component of onions) is readily available over-the-counter in pharmacies, there is a possibility that taking onion juice as a health supplement along with prescribing nifedipine prevent or treat cardiovascular disease such as hyperlipidemia, atherosclerosis and hypertension.Conclusion
Kaempferol significantly increased AUC0-∞ and Cmax of nifedipine after oral and intravenous administration. The increased bioavailability of nifedipine with kaempferol may be mainly due to the inhibition of the P-gp-mediated efflux transporter in the small intestine as well as the inhibition of CYP3A4-mediated metabolism in the small intestine or liver or both. Moreover, the decrease of total body clearance of nifedipine by kaempferol may also contribute to the increased bioavailability. In this study raised the awareness of the potential drug interactions with the concomitant use of kaempferol and nifedipine. The clinical significance of this finding needs to be further evaluated in future studies.
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