Amlodipine In Rats Research Articles

Effects of curcumin on the pharmacokinetics of amlodipine in rats and its potential mechanism

Context Hyperlipidaemia and hypertension are often treated together with curcumin and amlodipine. It is necessary to investigate the drug-drug interaction between curcumin and amlodipine. Objective The interaction between curcumin and amlodipine was investigated in rats and with rat liver microsomes. Methods The pharmacokinetics of amlodipine (1 mg/kg) was investigated in rats with or without curcumin pre-treatment (2 mg/kg), six rats in each group. The metabolic stability of amlodipine was investigated with rat liver microsomes. Results Curcumin significantly increased the C max (26.19 ± 2.21 versus 17.80 ± 1.56 μg/L), AUC(0-t) (507.27 ± 60.23 versus 238.68 ± 45.59 μg·h/L), and t1/2 (14.69 ± 1.64 versus 11.43 ± 1.20 h) of amlodipine (p < 0.05). The metabolic stability of amlodipine was significantly increased with the half-life time in rat liver microsomes increased from 34.23 ± 3.33 to 44.15 ± 4.12 min, and the intrinsic rate decreased from 40.49 ± 3.26 to 31.39 ± 2.78 μL/min/mg protein. Discussion and conclusions These results indicated that drug–drug interaction might appear during the co-administration of curcumin and amlodipine. The potential mechanism may be due to the inhibition of CYP3A4 by curcumin. Thus, this interaction should be given special attention in the clinic and needs further experiments to characterize the effect in humans.

Effects of atorvastatin on pharmacokinetics of amlodipine in rats and its potential mechanism

Atorvastatin combined with amlodipine (ALDP) can efficiently treat the hypertension with coronary heart disease. However, the drug-drug interaction between atorvastatin and ALDP are still unknown.This study investigates the effects of atorvastatin on the pharmacokinetics of ALDP in rats and clarifies its main mechanism.The pharmacokinetic profiles of oral administration of ALDP (1 mg/kg) in Sprague-Dawley rats, with or without pretreatment of atorvastatin (1.5 mg/kg/d for 7 d) were investigated. The effects of atorvastatin on the metabolism of ALDP were also investigated using rat liver microsomes.The results showed that atorvastatin could significantly increase the peak plasma concentration (from 18.28 ± 2.65 to 24.13 ± 1.96 ng/mL) and decrease the oral clearance (from 4.57 ± 1.15 to 1.79 ± 0.28 L/h/kg) of ALDP. In the rat liver microsome systems, the intrinsic clearance rate of ALDP was decreased by the pretreatment with atorvastatin (39.26 ± 2.1 vs. 33.24 ± 3.3 μL/min/mg protein).Those results indicated that atorvastatin could significantly affect the pharmacokinetic of ALDP, via inhibiting the metabolism of ALDP in rats.

Effects of Danshen tablets on pharmacokinetics of amlodipine in rats

Context: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with amlodipine (ALDP) for treating coronary heart disease.Objective: This study investigated the effects of DST on the pharmacokinetics of ALDP and the potential mechanism.Materials and methods: The pharmacokinetics of ALDP (1 mg/kg) in male Sprague–Dawley rats (n = 6), with or without pretreatment of DST (100 mg/kg for 7 d), were investigated using LC-MS/MS. The effects of DST on the metabolic stability of ALDP were also investigated using rat liver microsomes (RLM).Results: The results indicated that Cmax (16.25 ± 2.65 vs. 22.79 ± 2.35 ng/ml), AUC(0–t) (222.87 ± 59.95 vs. 468.32 ± 69.87 n gh/ml), and t1/2 (10.60 ± 1.05 vs. 14.15 ± 1.59 h) decreased significantly when DST and ALDP were co-administered, which suggested that DST might influence the pharmacokinetic behaviour of ALDP when they are co-administered. The metabolic stability of ALDP was also decreased (23.6 ± 4.7 vs. 38.9 ± 5.2) with the pretreatment of DST.Discussion and conclusions: This study indicated that DST could accelerate the metabolism of ALDP in RLM and change the pharmacokinetic behaviours of ALDP. Accordingly, these results showed that the herb–drug interaction between DST and ALDP might occur when they were co-administered. Therefore, the clinical dose of ALDP should be increased when DST and ALDP are co-administered.

Cardiotropic action of combined use of celecoxib and amlodipine in rats sicked on adjuvant arthritis coupled with arterial hypertension

Drug therapy of rheumatoid arthritis combined with arterial hypertension is among actual medical objectives. The complexity of pharmacological treatment of comorbid state is due to not only pathological process severity, insufficient efficacy and side effects of disease modifying and symptomatic drugs but also property of nonsteroidal anti-inflammatory drugs (NSAIDs) to aggravate already existed arterial hypertension in patients with rheumatoid arthritis or to increase pressure. Many hypotensive drugs loose or don’t manifest their activity when used in combination with NSAIDs. High risk of cardio toxicity is registered for one of NSAIDs group – coxibs. The cardio safety of combined use of coxibs and hypotensive drugs on the ground of comorbid pathology is studied not enough.&#x0D; These aspects had predefined the aim of this study – to investigate cardiotropic effects of celecoxib when administered in combinations with amlodipine on the ground of experimental rheumatoid arthritis coupled with arterial hypertension.&#x0D; Arterial hypertension was modeled in rats by method of salt load. On the basis of arterial hypertension rheumatoid arthritis was caused by full Freund adjuvant injection. Arterial blood pressure and heart rate registered on sphygmomanometer.&#x0D; It was found that comorbid state is followed by arterial hypertension and tachyarrhythmia. Celecoxib does not facilitate hypertension enhancing but leads to increasing heart rate. Amlodipine manifests specific pharmacological activity as hypotensive drug. The results obtained predefined opportunity of combined use of celecoxib with amlodipine on the ground of rheumatoid arthritis coupled with arterial hypertension.

Effects of triptolide on pharmacokinetics of amlodipine in rats by using LC–MS/MS

Context: Triptolide and amlodipine are often simultaneously used for reducing urine protein excretion after renal transplantation in China clinics.Objective: This study investigated the effects of triptolide on the pharmacokinetics of amlodipine in male Sprague–Dawley rats.Materials and methods: The pharmacokinetics of amlodipine (1 mg/kg) with or without triptolide pre-treatment (2 mg/kg/day for seven days) were investigated using a sensitive and reliable LC–MS/MS method. Additionally, the inhibitory effects of triptolide on the metabolic stability of amlodipine were investigated using rat liver microsome incubation systems.Results: The results indicated that when the rats were pre-treated with triptolide, the Cmax of amlodipine increased from 13.78 ± 3.57 to 19.96 ± 4.56 ng/mL (p < 0.05), the Tmax increased from 4.04 ± 1.15 to 5.89 ± 1.64 h (p < 0.05), and the AUC0–t increased by approximately 104% (p < 0.05), which suggested that the pharmacokinetic behaviour of amlodipine was affected after oral co-administration of triptolide. Additionally, the metabolic half-life was prolonged from 22.5 ± 4.26 to 36.8 ± 6.37 min (p < 0.05) with the pre-treatment of triptolide.Conclusions: In conclusion, these results indicated that triptolide could affect the pharmacokinetics of amlodipine, possibly by inhibiting the metabolism of amlodipine in rat liver when they are co-administered.

Effect of Ginkgo Leaf Tablets on the Pharmacokinetics of Amlodipine in Rats.

Ginkgo leaf tablet (GLT) is an effective traditional Chinese multi-herbal formula, which is often combined with amlodipine for treating senile hypertension in clinic. The aim of this study was to study the pharmacokinetics of amlodipine after oral administration of amlodipine and GLT and to investigate the potential for pharmacokinetic herb-drug interactions between GLT and amlodipine in rats. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method was developed for quantification of amlodipine in rat plasma. The accuracy, precision, linearity, selectivity and recovery were all within an acceptable range. Male Sprague-Dawley rats were randomly assigned to two groups: amlodipine group and amlodipine+GLT group. Plasma concentrations of amlodipine were determined at the designated time points after oral administration by using the developed LC-MS/MS method, and the main pharmacokinetic parameters were calculated and compared. As ginkgolides A, ginkgolides B, bilobalide, quercetin and kaempferol were the main components of GLT, the effects of these ingredients in GLT on metabolism of amlodipine were further investigated in rat liver microsomes. The pharmacokinetic parameters, maximum plasma concentration (C max), time to reach C max (T max), area under the concentration-time curve (AUC), area under the first moment plasma concentration-time curve (AUMC) and elimination half-life (t 1/2), of amlodipine were significantly increased in amlodipine+GLT group, which suggested that GLT may influence the pharmacokinetic behavior after oral co-administration with amlodipine. Amlodipine is metabolized by cytochrome P450 (CYP) 3A4, so it was speculated that GLT may change the pharmacokinetic parameters of amlodipine through modulating the metabolism of CYP3A4 enzymes. When ginkgolides B, bilobalide, or quercetin and amlodipine were co-incubated in the rat liver microsomes, the metabolic rate of amlodipine was prolonged to 533.1, 216.1 and 407.6min, respectively, from 73.7min. These results suggested that these components in GLT inhibit the metabolism of amlodipine. So it can be speculated that the herb-drug interactions between GLT and amlodipine resulted from inhibiting the metabolism of amlodipine by GLT when they were co-administered.

Effect of rhododendron flower juice on the bioavailability of amlodipine in rats

The aim of the study was to determine the effect of rhododendron flower juice on the bioavailability of Amlodipine in rats. This study was carried out in rats as a parallel design study. After the analysis of blood samples, it has been concluded that a component (s) of rhododendron flower juice inhibits the CYP3A4 mediated metabolism of Amlodipine. AUC was determined with the help of Trapezoidal rule. C max and T max were determined from the area under the plasma concentration-time curve. Statistical analysis was performed on the data obtained from both the group of rats. One way Analysis of Variance (ANOVA) from which Tukey-Kramer Multiple Comparisons Test was applied to the data obtained. This test compared all the parameters such as AUC, C max and T max without flower juice and after giving flower juice and the standard deviation of AUC of amlodipine with and without juice was found to be 14.25 and 10.44 respectively. AUC of the amlodipine after giving rhododendron flower juice to rats was significantly increased in comparison to the control group. The Overall result indicates that the oral bioavailability of amlodipine after giving rhododendron flower juice was increased as compared to the amlodipine with water.

Formulation and optimization of spray-dried amlodipine solid dispersion for enhanced oral absorption

Objective: To enhance the oral absorption of photosensitive amlodipine free base, which exhibits a slow dissolution rate and low permeability characteristics, an amorphous solid dispersion system was formulated and characterized.Material and methods: The solid dispersion was prepared by dispersing the amlodipine free base in excess dextrin (1:10 by weight) using a spray-drying technique in the presence of a minimum amount (0.9% w/w) of SLS as an absorption enhancer. The dextrin-based solid dispersion of amlodipine (Amlo-SD) was evaluated in term of formulation, characterization and in vivo absorption study, as well as the spray-drying process was also optimized.Results and discussion: The Amlo-SD particles were spherical with a smooth surface and an average particle size of 12.9 μm. Amlodipine was dispersed in an amorphous state and its content remained uniform in the Amlo-SD. The physicochemical stability of the Amlo-SD was maintained at room temperature for 6 months and the photostability was considerably improved. The dissolution of the Amlo-SD was much faster than that of amlodipine at pH 1.2 and 6.8. Amlo-SD produced significantly higher plasma concentrations of amlodipine in rats than amlodipine alone. Amlo-SD with and without SLS provided 2.8- and 2.0-fold increase in AUC, respectively: the difference seems to be attributed to a permeability enhancement effect by SLS.Conclusion: The Amlo-SD with SLS system is a potential formulation option for amlodipine.

Changes in the Pharmacokinetics of Rosiglitazone, a CYP2C8 Substrate, When Co-Administered with Amlodipine in Rats

Rosiglitazone maleate (RGM) is widely used for improving insulin resistance. RGM is a moderate inhibitor of cytochrome P450 2C8 (CYP2C8) and is also mainly metabolized by CYP2C8. The aim of this study was to determine whether the effect of RGM on CYP2C8 is altered by co-treatment with other drugs, and whether amlodipine camsylate (AC) changes the pharmacokinetics (PK) of RGM. Of the 11 drugs that are likely to be co-administered with RGM in diabetic patients, seven drugs lowered the IC50 value of RGM on CYP2C8 by more than 80%. In vitro CYP2C8 inhibitory assays of RGM in combination with drugs of interest showed that the IC50 of RGM was decreased by 98.9% by AC. In a pharmacokinetic study, Sprague-Dawley (SD) rats were orally administered 1 mg/kg of RGM following by single or 10-consecutive daily administrations of 1.5 mg/kg/day of AC. No significant changes in the pharmacokinetic parameters of RGM were observed after a single administration of AC, but the AUC and Cmax values of RGM were significantly reduced by 36% and 31%, respectively, by multiple administrations of AC. In conclusion, RGM was found to be affected by AC by in vitro CYP2C8 inhibition testing, and multiple dosing of AC appreciably changed the pharmacokinetics of RGM. These findings suggest that a drug interaction exists between AC and RGM.

Effects of Cyclosporine A and Itraconazole on Permeability, Biliary Excretion and Pharmacokinetics of Amlidipine

Cyclosporin A (CsA) is a P-glycoprotein (P-gp) inhibitor clinically used as an immunosuppressant. Itraconazole (ITZ) functions as an inhibitor of both the P-gp and CYP3A and is used as a fungistatic/fungicidal agent in human and veterinary medicine. The present studies were designed to investigate the effects of CsA and ITZ on 1) intestinal permeability of amlodipine (a calcium channel blocker used as a cardiovascular agent) in isolated rat everted gut sac model, and 2) biliary excretion and pharmacokinetics of amlodipine in rats. The concentrations of amlodipine in biosamples were measured by the liquid chromatograph mass spectrometer (LC/MS). Both CsA and ITZ significantly increased permeability of amlodipine in the ileum and jejunum of the rat everted gut sac model, and ITZ showed more potent than CsA in this model. Pretreatment of rats with ITZ increased plasma levels and biliary excretion of amlodipine in a dose-dependent manner. In contrast, pretreatment with CsA slightly decreased biliary excretion of amlodipine and made no changes in its plasma levels. In conclusion, ITZ increased in vitro permeability of amlodipine and its levels in plasma and bile in vivo. Whereas, CsA showed no significant effects on the levels of amlodipine in rat plasma and bile probably due to the potent inhibition of ITZ against both CYP3A and P-gp.

Troglitazone Thiol Adduct Formation in Human Liver Microsomes: Enzyme Knietics and Reaction Phenotyping

Troglitazone (TGZ) induced hepatotoxicity has been linked to cytochrome P450 (CYP)-catalyzed reactive metabolite formation. Therefore, the kinetics and CYP specificity of reactive metabolite formation were studied using dansyl glutathione (dGSH) as a trapping agent after incubation of TGZ with human liver microsomes (HLM) and recombinant human CYP proteins. CYP2C8 exhibited the highest rate of TGZ adduct (TGZ-dGS) formation, followed by CYP3A4, CYP3A5, and CYP2C19. The involvement of CYP2C8 and CYP3A4 was confirmed with CYP form-selective chemical inhibitors. The impact of TGZ concentration on the rate of TGZ-dGS formation was also evaluated. In this instance, two distinctly different profiles were observed with recombinant CYP3A4 and CYP2C8. It is concluded that both CYP3A4/5 and CYP2C8 play a major role in the formation of TGZ adduct in HLM. However, the contribution of these CYPs varies depending on their relative expression and the concentration of TGZ.

Comparative Effects of Pranidipine with Amlodipine in Rats with Heart Failure

The aim of the present study was to compare the cardioprotective properties of long-acting calcium channel antagonist pranidipine with amlodipine in rat model of heart failure induced by autoimmune myocarditis. Twenty-eight days after immunization the surviving rats were randomized for the oral administration of low-dose amlodipine (1 mg/kg/day), high-dose amlodipine (5 mg/kg/day), pranidipine (0.3 mg/kg/day) or vehicle (0.5% methylcellulose). After oral administration for 1 month, the animals underwent echocardiography and hemodynamic analysis. Histopathology, immunohistochemistry, and Western immunoblotting were carried out in the heart samples. Both pranidipine and high-dose amlodipine increased survival rate. Although the heart rate did not differ among the four groups, left ventricular end-diastolic pressure was significantly decreased and ±dP/dt was increased in the pranidipine- and high-dose amlodipine-treated rats, but not in low-dose amlodipine-treated rats. In comparison to amlodipine treatment, pranidipine treatment significantly reduced myocyte size and central venous pressure. Furthermore, both pranidipine and high-dose amlodipine treatment significantly reduced myocardial protein levels of atrial natriuretic peptide and inducible nitric oxide synthase, whereas pranidipine only significantly decreased tumor necrosis factor-α, and improved sarcoplasmic reticulum Ca²⁺ATPase2 protein levels. We conclude that pranidipine ameliorates the progression of left ventricular dysfunction and cardiac remodeling in rats with heart failure after autoimmune myocarditis in a lower dose when compared to amlodipine and which may be a clinically potential therapeutic agent for the treatment of heart failure.

Negligible pharmacokinetic interaction between oral DA-8159, a new erectogenic, and amlodipine in rats

A pharmacokinetic interaction between oral DA-8159 and amlodipine was evaluated in male Sprague-Dawley rats. In rats pretreated with troleandomycin (a main inhibitor of CYP3A1/2 in rats), the AUC(0-6 h) of amlodipine was significantly greater than the controls (34.5+/-6.01 compared with 28.0+/-4.70 microg min/ml), indicating that amlodipine is metabolized via CYP3A1/2 in rats. It was reported that the metabolism of DA-8159 and the formation of DA-8164 (a metabolite of DA-8159) were mainly mediated via CYP3A1/2 in rats, and amlodipine significantly inhibited the CYP3A2 in rats. Therefore, a pharmacokinetic interaction between the two drugs could be expected. However, after oral administration of DA-8159 at a dose of 30 mg/kg with or without oral amlodipine at a dose of 5 mg/kg to rats, the pharmacokinetic parameters of DA-8159 and DA-8164 were not significantly different between the two groups of rats. Similar results were also obtained from amlodipine between with and without DA-8159. The above data indicated that the pharmacokinetic interaction between oral DA-8159 and amlodipine was almost negligible in rats.

Effects of amlodipine once or twice daily on circadian blood pressure profile, myocardial hypertrophy, and beta-adrenergic signaling in transgenic hypertensive TGR(mREN2)27 rats.

The effects of amlodipine on blood pressure profiles, cardiac hypertrophy, and beta-adrenergic signal transduction were studied in transgenic hypertensive TGR(mREN2)27 rats (TGRs), which are characterized by an inverse circadian blood pressure rhythm. Cardiovascular parameters were monitored by radiotelemetry; beta-adrenoceptor density and function were measured by radioligand binding and by determination of beta-adrenergic stimulation of adenylyl cyclase. Ventricular weight and the activity of cardiac sarcolemmal 5-nucleotidase were used as measures of hypertrophy. Acute i.p. injection of amlodipine (1, 3, 10 mg/kg body weight) either at 8:00 or at 20:00 h dose-dependently reduced blood pressure irrespective of the dosing time. For long-term treatment, TGRs were divided into three groups: untreated; amlodipine, once-daily, 5 mg/kg; and amlodipine, twice daily, 2.5 mg/kg. Both treatment schedules resulted in decreased 24 h means in systolic and diastolic blood pressure and a reduction in ventricular hypertrophy but had no effects on cardiac beta-adrenergic signaling. Once-daily dose of amlodipine at 8:00 h decreased blood pressure predominantly during the daily resting period of the rats, whereas twice-daily dosing induced a bimodal blood pressure pattern. However, even after 5 weeks of treatment, typical circadian profiles could not be observed with either treatment, indicating a short duration of action of amlodipine in rats. Thus it remains an open question whether pharmacologic normalization of the circadian blood pressure pattern in TGRs will more effectively reduce myocardial hypertrophy and restore beta-adrenergic signaling than a reduction in 24-h blood pressure per se.

Quantitative determination of amlodipine in serum by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

A sensitive and specific liquid chromatographic method coupled with tandem mass spectrometry was developed for the quantification of amlodipine in human and rat serum, which is a dihydropyridine derivative with calcium antagonist activity. An atmospheric pressure chemical ionization interface was used as the ion source and the analysis was performed in the selected reactive monitoring (SRM) mode. Deuterated amlodipine was used as the internal standard, and serum samples were treated with diethyl ether extraction prior to analysis. Serum levels in the range 0.014-7.2 ng ml-1 were measured accurately by this method, and the lower limit of quantitation (LOQ) was 0.014 ng ml-1 using 1 ml of human serum. The accuracy was within 7% of the expected values. The intra-assay precision was less than 3% and the inter-assay precision was less than 6%. The method was applied to a pharmacokinetic study of amlodipine in rats, in which the measurable range was 0.14-72 ng ml-1 using 0.1 ml of serum because of a limitation on the sample volume.

Chronopharmacology of amlodipine in rats

The present study was undertaken to examine whether plasma concentrations of amlodipine, a calcium antagonist, and its diuretic effects vary with the time of dosage. Pharmacokinetic study; 20 mg/kg of amlodipine was given orally to rats at 10 am (day trial) or 10 pm (night trial), and blood samples were obtained during a 24-hour period. Pharmacodynamic study; two doses (10 and 20 mg/kg) of amlodipine were given orally at 10 am or 10 pm by a cross-over design, and urine was collected for 12 hours after dosage. Rats were maintained under condition of light from 7 am to 7 pm. The following results were obtained; The tmax of amlodipine was shorter and the Cmax was greater in the night trial than in the day trial. Its diuretic effects were greater in the night trial. These results suggest that the pharmacokinetic and pharmacodynamic profiles of amlodipine vary with its time of dosage.

Effects of Amlodipine on Orcadian Rhythms in Blood Pressure, Heart Rate, and Motility: A Telemetric Study in Rats

In male Wistar rats [light(L): 07:00-19:00 h, dark(D): 19:00-07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED50 values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.