Plasma Concentrations Of Amlodipine Research Articles

Evaluation of pharmacokinetics and safety with bioequivalence of Amlodipine in healthy Chinese volunteers: Bioequivalence Study Findings.

Background and ObjectiveAmlodipine, a main series of L‐type calcium channel blockers (CCBs), exerts potent antihypertensive effects. The aim of this trial was to explore the pharmacokinetics (PK) and safety with bioequivalence of orally administered Amlodipine provided by two sponsors in healthy volunteers (HVs).MethodsTwo separate randomized, open‐label, single‐dose, crossover‐design studies were conducted: a fasting study (n = 24) and a fed study (n = 24). In each study, HVs were randomized to Fangming Pharmaceutical Group (Test, T) followed by NORVASC® (Reference, R), or vice versa. Each study subject received a 5‐mg Amlodipine tablet with a 15‐day washout. The plasma concentrations of Amlodipine were measured using a LC‐MS/MS method, and PK parameters were determined by noncompartmental model.ResultsForty‐eight healthy volunteers were enrolled. And overall demographics were as follows: the fasting study: female (n = 16/24), age (18‐54 years), weight (47‐76 kg), and BMI (19.5‐26.0). The fed study: female (n = 16/24), age (20‐49 years), weight (45.5‐69 kg), and BMI (19.1‐25.0). All PK endpoints met the pre‐specific criteria for PK equivalence. In fasting subjects, the maximum plasma concentration (C max) was 3.881 ± 0.982 ng/mL at 6 hours (median) of sponsor T, and 4.042 ± 1.147 ng/mL at 6 hours (median) of sponsor R. In fed subjects, C max was 3.312 ± 0.789 ng/mL at 6 hours (median) of sponsor T, and 3.392 ± 0.902 ng/mL at 5 hours (median) of sponsor R. Both fasting and fed studies achieved a plausible bioequivalence.ConclusionsAmlodipine is well tolerated and have a favorable safety profile. The observed adverse events were mild (the severity was assessed according to the Common Terminology Criteria for Adverse Events [version CTCAE4.03]) and all of them were recovered without severe sequences. And the bioequivalence is achieved under fasting and fed conditions, supporting the demonstration of biosimilarity.

Pharmacokinetic Drug Interactions Between Amlodipine, Valsartan, and Rosuvastatin in Healthy Volunteers

Amlodipine, valsartan, and rosuvastatin are among the medications widely coadministered for the treatment of hyperlipidemia accompanied by hypertension. The aim of this study was to investigate the possible pharmacokinetic drug-drug interactions between amlodipine, valsartan, and rosuvastatin in healthy Korean male volunteers. In this phase 1, open-label, multiple-dose, two-part, two-period, fixed-sequence study, the enrolled subjects were randomized into two parts (A and B). In part A (n = 32), each subject received one fixed-dose combination (FDC) tablet of amlodipine/valsartan 10mg/160mg alone for 10 consecutive days in period I, and the same FDC for 10days with concomitant 7-day administration of 20mg rosuvastatin in period II. In part B (n = 25), each subject received rosuvastatin alone for 7days in period I, and the FDC for 10days with concomitant 7-day administration of rosuvastatin in period II. In both parts, there was a 12-day washout between periods. Serial blood samples were collected for up to 72h for amlodipine and rosuvastatin, and for up to 48h for valsartan after the last dose of each period. The plasma concentrations of amlodipine, valsartan, and rosuvastatin were determined by using liquid chromatography-tandem mass spectrometry. Fifty-seven subjects were enrolled; 30 and 25 subjects completed part A and part B, respectively. The geometric mean ratios and 90% confidence intervals for the maximum plasma concentration at steady state (Cmax,ss) and the area under the plasma concentration-time curve over the dosing interval at steady state (AUCτ,ss) were 0.9389 (0.9029-0.9763) and 0.9316 (0.8970-0.9675) for amlodipine, 0.7698 (0.6503-0.9114) and 0.7888 (0.6943-0.8962) for valsartan, and 0.9737 (0.8312-1.1407) and 0.9596 (0.8826-1.0433) for rosuvastatin, respectively. Of the 57 subjects enrolled in this study, 10 subjects experienced 13 adverse events (AEs); no severe or serious AEs were reported. When amlodipine, valsartan, and rosuvastatin were coadministered to healthy volunteers, the pharmacokinetic exposure to valsartan was decreased, but no change in exposure to amlodipine and rosuvastatin occurred. All treatments were well tolerated. https://cris.nih.go.kr CRIS KCT0001660. KyungDong Pharmaceutical Corp. Ltd., Seoul, Republic of Korea.

Effect Of epigallocatechin-3-gallate on the pharmacokinetics of amlodipine in rats

This study investigates the effect of epigallocatechin-3-gallate (EGCG), a major ingredient of green tea, on the pharmacokinetics of amlodipine in rats.The pharmacokinetics of orally administered amlodipine (1 mg/kg) with or without EGCG pretreatment (30 mg/kg/day for 10 days) were investigated. Plasma concentrations of amlodipine were determined by using a sensitive and reliable liquid chromatography with tandem mass spectroscopy (LC-MS/MS) method. The effects of EGCG on the metabolic stability of amlodipine were investigated by using rat liver microsome incubation systems.The results indicated that when the rats were pretreated with EGCG, the Cmax of amlodipine increased from 16.32 ± 2.57 to 21.44 ± 3.56 ng/mL (p < 0.05), the Tmax decreased from 5.98 ± 1.25 to 4.01 ± 1.02 h (p < 0.05), and the AUC0–t increased from 258.12 ± 76.25 to 383.34 ± 86.95 μg h L−1 (p < 0.05), which suggested that the pharmacokinetic behavior of amlodipine was affected after oral co-administration of EGCG. Additionally, the metabolic half-life was prolonged from 31.3 ± 5.6 to 52.6 ± 7.9 min (p < 0.05) with the pretreatment of EGCG.It can be speculated that the drug-drug interaction between EGCG and amlodipine might occur, which might have resulted from the metabolism inhibition of amlodipine by EGCG when they were co-administered.

Therapeutic drug monitoring of amlodipine and the Z-FHL/HHL ratio: Adherence tools in patients referred for apparent treatment-resistant hypertension.

Non-adherence to antihypertensives is a cause of 'pseudo-treatment-resistant' hypertension. To determine whether monitoring plasma amlodipine concentrations and inhibition of angiotensin-converting enzyme (ACE) can be adjunct adherence tools. Patients with hypertension who were prescribed enalapril and amlodipine were enrolled. Blood pressures (BPs) were monitored and an adherence questionnaire was completed. Steady-state amlodipine was assayed using liquid chromatography-mass spectrometry and degree of ACE inhibition using the Z-FHL/HHL (z-phenylalanine-histidine-leucine/hippuryl-histidine-leucine) ratio. One hundred patients (mean (standard deviation) age 50.5 (12) years, 46% male) were enrolled. Based on plasma assays, 26/97patients (26.8%) were unsuppressed by enalapril and 20/100 (20%) were sub-therapeutic for amlodipine. There were significant BP differences based on plasma levels of the medication: 21/20 mmHg lower in the group with suppressed ACE and 26/20 mmHg in the group with steady-state amlodipine concentrations. Monitoring antihypertensive adherence by assaying plasma medication concentrations is a feasible option for evaluating true v. pseudo-resistant hypertension.

Factors Influencing the Relationship Between the Dose of Amlodipine Required for Blood Pressure Control and Change in Blood Pressure in Hypertensive Cats.

BackgroundHypertension is a common problem in elderly cats. In most cats, systolic blood pressure (SBP) of <160 mmHg is achieved in response to amlodipine besylate at either 0.625 or 1.25 mg q24h. The individual cat factors determining dose requirement dose have not been explored.AimsTo determine whether individual cat factors influence the dose of amlodipine required to achieve adequate blood pressure control and to determine whether factors other than the prescribed dose of drug alter the achieved plasma amlodipine concentrations.MethodsFifty‐nine hypertensive cats that required 0.625 mg (A) and 41 cats that required 1.25 mg (B) amlodipine to reach a target SBP of <160 mmHg were identified, and plasma amlodipine concentrations were determined. Comparisons were made between groups, and multivariable linear regression models were performed to investigate predictors of antihypertensive response.ResultsCats that required a greater dose of amlodipine had significantly higher SBP at diagnosis of hypertension (A: (median [25th, 75th percentile]) 182 [175,192] mmHg; B: 207 [194,217] mmHg, P < .001), but comparable blood pressure was achieved after treatment. Plasma amlodipine concentrations were directly related to the dose of amlodipine administered. At diagnosis, cats in group B had significantly lower plasma potassium concentration (A: 4.1 [3.8,4.5]; B: 3.8 [3.6,4.2] mEq/L, P < .01). Weight did not differ between groups. The decrease in SBP was directly and independently associated with the SBP at diagnosis and the plasma amlodipine concentration.Conclusions and Clinical ImportanceCats with higher blood pressure at diagnosis might require a greater dose of amlodipine to control their blood pressure adequately. Differences in amlodipine pharmacokinetics between cats do not seem to play a role in the antihypertensive response.

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.

CYP3A activity based on plasma 4β-hydroxycholesterol during the early postpartum period has an effect on the plasma disposition of amlodipine

This study aimed to evaluate plasma 4β-hydroxycholesterol as an endogenous marker of CYP3A4/5 activity in early postpartum women and its impact on the plasma disposition of amlodipine. Twenty-seven early postpartum women treated with amlodipine for pregnancy-induced hypertension were enrolled. The plasma concentration of 4β-hydroxycholesterol and its ratio to cholesterol in postpartum and in non-perinatal women were evaluated. The predose plasma concentration of amlodipine was determined at steady state. The medians of the plasma 4β-hydroxycholesterol concentration at day 0–3 and 8–21 after delivery were 146 and 161 ng/mL, respectively. No significant difference was observed in the plasma concentration of 4β-hydroxycholesterol between the postpartum periods. The plasma concentration of 4β-hydroxycholesterol and its ratio to cholesterol in postpartum women were significantly higher than those in non-perinatal women. A large individual variability was observed in the dose-normalized plasma concentration of amlodipine in early postpartum women. A weak negative correlation was observed between the dose-normalized plasma concentration of amlodipine and the plasma concentration of 4β-hydroxycholesterol. In conclusion, early postpartum women possessed higher CYP3A activity based on plasma 4β-hydroxycholesterol and had a large pharmacokinetic variability in amlodipine. CYP3A activity during the early postpartum period had an effect on the plasma disposition of amlodipine.

Effects of genetic factors on the pharmacokinetics and pharmacodynamics of amlodipine in primary hypertensive patients.

The aim of the present study was to explore the effects of common genetic polymorphisms of cytochrome P450 (CYP)3A4, CYP3A5, cytochrome P450 oxidoreductase (POR) and multidrug resistance protein 1 (MDR1) on the pharmacokinetics and pharmacodynamics of amlodipine in primary hypertensive patients. The mild-to-moderate essential hypertension patients were recruited to complete the genotyping of CYP3A4, CYP3A5, POR and MDR1 by sequencing. After a 1-week placebo washout period, the subjects received 5 mg oral amlodipine daily for 4 weeks. Serial blood samples were collected prior to the last dosing, and 2, 6 and 24 h post-dosing. Blood pressures were measured prior and subsequent to dosing, and the demographical data were also collected. The blood samples were collected for laboratory testing. The plasma concentrations of amlodipine were determined by high-performance liquid chromatography/tandem mass spectrometry. A total of 60 patients, including 31 males and 29 females, completed the 4-week treatment. The plasma concentration of amlodipine in females at each time point was significantly higher compared to males (P<0.05). However, no significant gender differences existed in antihypertensive efficacy. The genetic polymorphisms of MDR1 C3435T had a certain impact on the plasma concentration of amlodipine, but did not affect its antihypertensive efficacy (P>0.05). The genetic polymorphisms of CYP3A4*1G, CYP3A5*3 and POR A503V showed no impact on plasma concentration and efficacy of amlodipine (P>0.05). Gender and MDR1 gene polymorphism may affect the plasma concentration of amlodipine in hypertensive patients. However, there was no impact on the efficacy of amlodipine.

Amlodipine passage into breast milk in lactating women with pregnancy-induced hypertension and its estimation of infant risk for breastfeeding.

Few clinical reports have been published on amlodipine passage into breast milk in lactating women. The aims of this study were to evaluate the plasma concentration of amlodipine and its passage into breast milk in lactating women with pregnancy-induced hypertension and to estimate the risk for breastfeeding infants. Thirty-one lactating women receiving oral amlodipine once daily for pregnancy-induced hypertension were enrolled. Pre-dose plasma and milk concentrations of amlodipine were determined at day 6 or later after starting the medication. Relative infant dose (RID) as an infant risk for breastfeeding was calculated by dividing the infant dose via milk by the maternal dose. The mean maternal dose of amlodipine was 6.0 mg. The medians of the plasma and milk concentrations of amlodipine were 15.5 and 11.5 ng/mL, respectively. Interindividual variation was observed in the amlodipine dose and body weight-adjusted milk concentrations (interquartile range [IQR], 96.7-205 ng/mL per mg/kg). The median and IQR of the amlodipine concentration ratio of milk to plasma were 0.85 and 0.74 to 1.08, respectively. The medians of infant birth weight and daily amlodipine dose via milk were 2170 g and 4.2 μg/kg, respectively. The median of the RID of amlodipine was 4.2% (IQR, 3.1%-7.3%). Lactating women with pregnancy-induced hypertension had higher plasma concentrations of amlodipine during the early postpartum period. Oral amlodipine transferred into breast milk at the same level as that of plasma. However, the RID of amlodipine in most patients was less than 10%.

Negligible Pharmacokinetic Interaction of Red Ginseng and Antihypertensive Agent Amlodipine in Sprague-Dawley Rats

Red ginseng (RG) is the top-selling functional food in Korea, but is not recommended for use in hypertensive patients. This study was performed to determine the pharmacokinetic (PK) interaction between RG and amlodipine, an antihypertensive drug. RG (0, 0.5, 1, or 2 g/kg/d) was administered orally for 2 wk, and then amlodipine (10 mg/kg) was given orally, to Sprague-Dawley (SD) rats. Blood was collected at 0.08, 0.25, 1, 1.5, 2, 3, 6, 12, and 24 h after amlodipine administration. In intravenous (iv) study, RG (0, 1, or 2 g/kg/d) was administered orally to SD rats for 2 wk, followed by amlodipine (2 mg/kg) intravenously (iv). Plasma concentrations of amlodipine were analyzed using a high-pressure liquid chromatography–tandem mass system (LC-MS/MS). Oral administration of amlodipine produced an increase of time to maximum plasma concentration (tmax: 2.6, 4.1, 8.3, and 8.9 h at 0, 0.5, 1, and 2 g/kg/d, respectively), and a decrease of maximum plasma concentration (Cmax: 278.5, 212.4, 232.1, and 238.7 ng/ml at 0, 0.5, 1, and 2 g/kg/d, respectively.). However, the area under the concentration–time curve from time 0 to 24 h measurable concentration (AUC0-24 h was 3487.4, 2895.4, 3158.2, and 3495 ng/h/ml at 0, 0.5, 1, and 2 g/kg/d respectively) was not significantly changed among the different dose groups. Administration of amlodipine iv produced no significant changes in the apparent terminal half-life, volume of distribution, and AUC0-24 hr among the different dose groups. These results suggest that RG induced negligible influence on amlodipine pharmacokinetically in rats.

Effects of Dividing Amlodipine Daily Doses on Trough Drug Concentrations and Blood Pressure Control Over a 24-Hour Period

BackgroundIn the treatment of hypertension, once-daily administration of long-acting antihypertensive drugs has been recommended for the improvement of treatment adherence; however, it is unclear whether dividing daily doses has the additional benefit of more ideal blood pressure (BP) control over a 24-hour period. ObjectiveThe aim of the study was to investigate whether dividing a 10-mg daily dose of amlodipine, a long-acting calcium channel blocker, is associated with increased trough plasma amlodipine concentrations, reduced arterial stiffness, and improved BP control over a 24-hour period. MethodsOutpatients with essential hypertension were included this open-label, 2-period crossover study. The patients were administered amlodipine 10 mg/d in 2 divided doses for 8 weeks. At week 4, blood was collected just before amlodipine administration for the evaluation of trough plasma amlodipine concentrations. At week 8, 24-hour, daytime, nighttime, and early morning BP, as well as arterial stiffness, were measured using ambulatory BP monitoring (ABPM) and cardio-ankle vascular index (CAVI), respectively. In the subsequent study period, amlodipine 10 mg/d was administered once daily, and the same tests were performed at the same timings as in period 1. ResultsTen patients were enrolled (7 men, 3 women; mean age, 61.0 [15.3] years). Mean 24-hour BP with twice-daily administration was not significantly lower than that with once-daily administration (129.7 [7.3]/80.1 [7.9] mm Hg vs 130.5 [11.8]/80.1 [7.9] mm Hg, respectively). Similarly, there were no significant differences in daytime, nighttime, or early morning BP between twice- and once-daily administration. In addition, the differences in trough plasma amlodipine concentrations (22.37 [7.66] ng/mL vs 20.57 [8.22] ng/mL) and CAVI values (8.2 [1.8] vs 8.5 [1.0]) were not significantly different between twice- and once-daily administration. ConclusionsAdministering amlodipine in 2 divided doses was not associated with increased trough plasma amlodipine concentrations, reduced arterial stiffness, or improved BP control over a 24-hour period in patients with essential hypertension. UMIN Clinical Trials Registry no. UMIN000003914.

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.

Comparison of Pharmacokinetic Characteristics and the Safety between Amlodipine Maleate Tablet 5 mg and Amlodipine Besylate Tablet 5 mg

1 Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Seoul, Korea, University of Ulsan College of Medicine, School of Military Medicine, The First Republic of Korea Army, Department of Clinical Pharmacology and Therapeutics, Inje University Pusan Paik Hospital, Pusan, Korea, 5 Division of Clinical Pharmacology, Clinical Trials Center, Pusan National University Hospital, Division of Clinical Pharmacology, Clinical Trial Center, Samsung Medical Center, Technical research center, CKD research institute, Chong Kun Dang Pharmaceutical Co, Ltd Background: Amlodipine is a third-generation dihydropyridine calcium channel blocker for treating hypertension. Though marketed primarily as a besylate salt, there have been some efforts to find other comparable salts. Among them, maleate is the salt that has been considered favorable for many drugs. The aim of this study was to compare the pharmacokinetics, as well as safety and tolerability of amlodipine maleate with amlodipine besylate. Methods: This study was open, randomized, two-period crossover design investigated in twelve healthy male volunteers over a 144 h period after administrating two forms of amlodipine 5 mg, respectively. Each period was separated with 2 weeks. Plasma concentrations of amlodipine were determined by liquid chromatography-tandem mass spectrometry. Safety profiles were assessed by vital signs, physical examinations, electrocardiograms, laboratory testing and adverse events monitoring. Results: All subjects were completed this study. Geometric mean ratios (GMRs) of amlodipine maleate/amlodipine besylate of Cmax and AUClast for amlodipine were 0.92 (90 % confidence interval, 0.81 ∼ 1.05) and 1.05 (0.96 ∼ 1.16), respectively. No serious adverse events were reported, and no clinically relevant changes were observed in safety profiles during this trial. Conclusion: Pharmacokinetics, tolerability and the safety were comparable between amlodipine maleate and amlodipine besylate in healthy individuals.

Effect of Amlodipine in Human Internal Mammary Artery and Clinical Implications

Graft spasm remains challenging in CABG (coronary artery bypass grafting) surgery. We investigated the inhibitory effect of a dihydropyridine calcium antagonist amlodipine on the vasoconstriction mediated by potassium chloride (KCl), human urotensin-II (hU-II), and U46619 in human internal mammary artery (IMA) from patients undergoing CABG. Isolated IMA rings (n = 78, taken from 42 patients) were studied in organ baths in two ways: the relaxing effect of amlodipine on vasoconstrictor-induced precontraction by KCl, hU-II, and U46619 and the depressing effect of amlodipine on the contraction. Amlodipine caused full relaxation in KCl-contracted (98.0% ± 2.1%), in hU-II-contracted (98.5% ± 2.4%), and in U46619-contracted (96.3% ± 1.3%) IMA rings (n = 8) with 15.5-fold higher potency to KCl than to hU-II (effective concentration causing 50% of maximal response [EC(50)]: -8.17 ± 0.28 vs -6.98 ± 0.01 log M, p < 0.001) and 19.5-fold that to U46619 (EC(50): -8.17 ± 0.28 vs -6.88 ± 0.08 log M, p < 0.001). Pretreatment of IMA with plasma concentrations of amlodipine (-6.6 log M) significantly depressed subsequent contraction to KCl (from 20.8 ± 2.5 mN to 7.6 ± 3.0 mN, p = 0.004) and hU-II (from 14.1 ± 4.2 mN to 3.8 ± 2.0 mN, p = 0.026), but did not significantly affect the contraction to U46619. We conclude that in human IMA amlodipine has a potent inhibitory effect on the vasoconstriction mediated by a variety of vasoconstrictors. Thus, use of amlodipine in CABG patients is favored in treating and preventing graft spasm.

Inhibition of Vasoconstriction by Amlodipine in Human Internal Mammary Arteries Used as Bypass Grafts

Graft spasm remains challenging in coronary artery bypass grafting (CABG). We studied the inhibitory effect of a dihydropyridine calcium antagonist amlodipine in 70 human internal mammary artery (IMA) segments from 34 patients undergoing CABG in organ baths in two ways: the relaxing effect of amlodipine on vasoconstrictor‐induced precontraction by potassium chloride (KCl), human urotensin II (hU‐II), and U46619 and the depressing effect of amlodipine on the contraction. Amlodipine caused full relaxation in KCl (98.0±2.1%)‐ and hU‐II (98.5±2.4%)‐ but not in U46619‐contracted IMA rings (n=8) with 15.5‐fold higher potency to KCl than to hU‐II (EC50: −8.17±0.28 vs. −6.98±0.01 logM, p&lt;0.001). Pretreatment of IMA with plasma‐concentrations of amlodipine (−7.6 and −6.6 logM, n=6) significantly depressed subsequent contraction to KCl (from 20.8±2.5 to 16.6±2.6 mN and from 20.8±2.5 to 7.6±3.0 mN, p&lt;0.05) and hU‐II (from 14.1±4.2 to 11.4±3.7 mN and from 14.1±4.2 to 3.8±2.0 mN, p&lt;0.05) but not to U46619. Thus, in human IMA, amlodipine has a selective inhibitory effect on the vasoconstriction mediated by vasoconstrictors with high potency on KCl and hU‐II and amlodipine may be effectively used in CABG patients for treatment and prevention of graft spasm.Supported by Tianjin Municipal Sci &amp; Tech Com (09ZCZDSF04200); Ministry of Sci &amp; Tech, China (2009DFB30560); Providence SVMF, OR &amp; Hong Kong GRF 465107, 478909.

Treatment of Feline Hypertension With Transdermal Amlodipine: A Pilot Study

This prospective study evaluated transdermal amlodipine for the control of hypertension in six cats. Cats were treated with oral amlodipine until blood pressures decreased to <180 mm Hg. They were maintained on this dose for 7 days and then administered identical doses of transdermal amlodipine for 7 days. Oral amlodipine decreased pressure by a median of 73 mm Hg, which subsequently increased by 20 mm Hg after 7 days of transdermal amlodipine. Plasma concentrations of amlodipine were measured after oral and transdermal dosing. Additional studies are needed to determine dosing, pharmacokinetics, and efficacy.

Single-Dose, Randomized, Crossover Bioequivalence Study of Amlodipine Maleate versus Amlodipine Besylate in Healthy Volunteers

Amlodipine, marketed primarily as a besylate salt, is a calcium channel blocker used for treating essential hypertension. Amlodipine maleate is another salt that is considered, in terms of pharmacokinetics and pharmacodynamics, similar to amlodipine besylate. This open, randomized, two-period crossover trial has investigated in 24 healthy volunteers over a 144 h period the bioequivalence of amlodipine maleate tablets 10 mg versus amlodipine besylate tablets (Norvasc® 10 mg). Plasma amlodipine concentrations were assessed by ultra performance liquid chromatography interfaced with a double quadrupole mass spectrometer. The area under the curve total (AUCt) and the area under the curve to infinity (AUCinf) values, peak plasma concentration (Cmax), and time to attain peak (tmax) were not statistically different between the two drugs. AUCt and AUCinf values were higher (p < 0.05) in females than in males. The tolerability profile was comparable for the two salts of amlodipine. These findings indicate that amlodipine maleate and besylate are bioequivalent and were well tolerated, which suggests that the plasma kinetics of amlodipine depend on the properties of the molecule itself. Hence, the two salts investigated could be used interchangeably in clinical practice.

CLINICAL AND PHARMACOKINETIC EQUIVALENCE OF ORIGINAL AND GENERIC AMLODIPINE IN PATIENTS WITH MILD-TO-MODERATE ARTERIAL HYPERTENSION

Aim. To study clinical equivalence of two amlodipines under the control of their plasma levels and evaluate their pharmacoeconomical efficacy in patients with arterial hypertension (AH). Material and methods. 31 patient with AH were included in the study (14 men and 17 women). 21 (66 %) patients had AH of 1 stage and 10 (34 %) patients had AH of 2 stage. All patients were 39-81 y.o. (average - 60 y.o.) with AH duration 0,5-43 years (average - 17,9 years). Antihypertensive effect of Amlorus (Synthesis, Russia) and Norvasc (Pfizer, USA) was evaluated in the study. Blood pressure (BP), amlodipine plasma levels (by liquid chromatography with mass spectrometry) and side effects were registered before and after 2, 4 and 6 weeks of therapy. Hydrochlorothiazide 25 mg/d was added if the monotherapy with amlodipine10 mg/d had not been efficient. Therapy with the second studied amlodipine followed the therapy with the first drug. Results. Both drugs provided similar plasma amlodipine concentrations with significant BP reduction. 96,6 % and 90 % of patients reached BP target level (<140/90 mm Hg) after 6 weeks of Amlorus and Norvasc therapy, respectively. Hydrochlorothiazide was needed in 23,3 % and 26,7 % of patients taking Amlorus and Norvasc, respectively. Cost of Amlorus therapy per patient was 221 rbl/month in comparison with cost of 727 rbl/month for Norvasc therapy. Conclusion. Generic Amlorus showed clinical and pharmacokinetic equivalency with an original amlodipine Norvasc and lower cost of therapy.

Effect of CYP3A53 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects

1,4-Dihydropyridine calcium channel blockers, including amlodipine, are mainly metabolized by cytochrome P450 (CYP) 3A. We investigated the effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean male subjects. Forty healthy male participants were enrolled and genotyped for the CYP3A5*3 gene. Each subject ingested a 5-mg dose of amlodipine, and plasma amlodipine concentrations were measured for 144 hours after dosing. Blood pressure and pulse rate were also measured for pharmacodynamic analysis. Among the 40 volunteers, 24 were CYP3A5*3/*3 carriers and 16 were CYP3A5*1 carriers (CYP3A5*1/*1 in 2 and CYP3A5*1/*3 in 14). The difference in the oral clearance of amlodipine approached statistical significance between the 2 major genotype groups, with CYP3A5*1 carriers (27.0 +/- 8.2 L/h) showing 20% lower clearance than CYP3A5*3/*3 carriers (32.4 +/- 10.2 L/h) (P = .063). However, the mean area under the plasma concentration-time curve of amlodipine was 200.9 +/- 61.9 ng . h/mL for CYP3A5*1 carriers and 167.6 +/- 45.0 ng . h/mL for CYP3A5*3/*3 carriers (P = .029). Moreover, the peak plasma concentration was significantly higher in CYP3A5*1 carriers (3.8 +/- 1.1 ng/mL) than in CYP3A5*3/*3 carriers (3.1 +/- 0.8 ng/mL) (P = .037). Pharmacodynamically, blood pressure and pulse rate were not significantly different between the 2 groups. CYP3A5*3/*3 carriers exhibited lower plasma amlodipine concentrations than CYP3A5*1 carriers. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of amlodipine and provides a plausible explanation for interindividual variability in amlodipine disposition.

A Case of Amlodipine Overdose

A case of severe amlodipine overdose with only mild symptoms is described. Plasma concentrations of amlodipine were measured in serial samples by gas chromatography. There was no concomitant overdose. The present case is compared with previous reported cases of amlodipine overdose where patients all developed severe symptoms. We conclude that amlodipine overdose does not always cause severe symptoms.