amlodipine Norvasc
Importance of metabolic stability and hepatic distribution to the pharmacokinetic profile of amlodipine.

Walker DK, Humphrey MJ, Smith DA.

Department of Drug Metabolism, Pfizer Central Research, Sandwich, UK.

1. In an isolated perfused rat liver (IPRL) model, the extensive hepatic uptake and subsequent slow redistribution of amlodipine into the perfusate have been demonstrated. The apparent liver volume for amlodipine was 920 ml compared with 38ml for nitrendipine. 2. Metabolism is the major clearance mechanism of amlodipine and nitrendipine in animals and man. In the IPRL, the intrinsic (metabolic) clearance and first-pass extraction values for amlodipine are similar to those of nitrendipine. This is in contrast with in vitro metabolic stability data in rat liver microsomes which indicate about 40-fold greater metabolic stability for amlodipine. 3. The discrepancy between relative clearance rates for the two preparations may be explained by consideration of the hepatic volume of the two compounds, with the higher liver volume of amlodipine amplifying the whole organ clearance.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8009887&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Biochemical changes during amlodipine treatment in hypertensive patients.

Ahaneku JE, Taylor GO, Walker O, Agbedana EO, Sowunmi A, Salako LA.

Department of Biochemistry and Cell Biology, National Institute of Health, Tokyo, Japan.

Twenty adult hypertensive patients mean age (52 (1.73) y) were treated with amlodipine 5 mg (8 patients) and 10 mg (12 patients) once daily for 12 weeks. There was a reduction in sitting and standing diastolic and systolic blood pressures in male and female patients. Plasma calcium, sodium, potassium, total proteins, albumin, globulins, phosphate, chloride, urea and haematological parameters were not significantly altered by amlodipine therapy in any patient. An increase in creatinine level was noted, which was not related to kidney dysfunction. We conclude that amlodipine 5 mg or 10 mg once daily is effective in male and female patients, and it does not alter biochemical and haematological values in hypertensive African patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8070506&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Enantioselective gas chromatographic assay with electron-capture detection for amlodipine in biological samples.

Scharpf F, Riedel KD, Laufen H, Leitold M.

R & D Laboratories, Pfizer Mack, Illertissen, Germany.

A sensitive enantioselective gas chromatographic assay has been developed for amlodipine, 2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine, a calcium channel blocking therapeutic agent. The assay involves conversion of the (+)-(R)- and (-)-(S)-enantiomers of amlodipine into their acyl derivatives with the chiral reagent (+)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride (Mosher's reagent). Peak separation after chromatography of the diastereomers was larger than 85%, and the lower limit of detection in blood plasma was 0.02 ng/ml for each enantiomer. The method has been used for the measurement of amlodipine enantiomers in human, rat and dog plasma, and in various organs of the rat.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8081468&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Antihypertensive effect of amlodipine and lack of interference with cyclosporine metabolism in renal transplant recipients.

Toupance O, Lavaud S, Canivet E, Bernaud C, Hotton JM, Chanard J.

Nephrology Service, University Hospital, Reims, France.

The catabolism of various calcium channel blockers through cytochrome P-450 is heterogeneous and may be modified by concomitant use of cyclosporin A. In an open study we investigated the antihypertensive effect and clinical tolerance of the dihydropyridine amlodipine and its effects on cyclosporine kinetics in stable hypertensive renal transplant recipients not taking corticosteroids. Ten adult hypertensive patients grafted for 21.4 +/- 8.9 months and well stabilized with normal renal function were included in the study. Renal artery stenosis was ruled out by normal Doppler echography. After 2 weeks of placebo, amlodipine was started at a daily dose of 5 mg. The dose was then adjusted to 10 mg if necessary. Blood and urine chemistries and whole-blood cyclosporine trough levels were measured weekly. Cyclosporine kinetics were determined on a hourly basis before amlodipine administration and after 4 weeks of treatment. Normal blood pressure was obtained with the use of 5 mg/d amlodipine in 7 patients and 10 mg/d in 3, diastolic blood pressure decreasing from 98.7 +/- 3.8 to 81.3 +/- 9.1 mm Hg (P = .0007). Heart rate slightly increased by 10% (P < .02). The drug was well tolerated, and only minor ankle edema was found in 3 patients. Cyclosporine doses were not modified and cyclosporine levels remained unchanged throughout the study. Cyclosporine kinetic parameters were not significantly different at the beginning and end of the study. Bioequivalence was demonstrated indicating that cyclosporine biotransformation was not altered by the concomitant administration of amlodipine.(ABSTRACT TRUNCATED AT 250 WORDS)

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amlodipine Norvasc
Effect of chronic blood pressure reduction on soleus muscle contractile properties in spontaneously hypertensive rats.

Gray SD, Carlsen RC, Atherley R.

Department of Human Physiology, School of Medicine, University of California, Davis 95616.

Soleus muscle in Wistar-Kyoto rats (WKY), as well as in most normotensive mammals, is highly fatigue resistant. In 6-mo-old spontaneously hypertensive rats (SHR), however, soleus muscle generates less specific force and experiences a more rapid rate of fatigue than in age-matched WKY. The present experiments tested the hypothesis that antihypertensive treatment with hydralazine or amlodipine would shift the contractile force and fatigue resistance profile of SHR soleus toward that which characterizes WKY. Hydralazine was given via the drinking water (100 mg/l) and amlodipine via the food (1 g/4 kg rat chow) to two separate groups of animals, starting at the age of 16 wk. At 24-26 wk of age soleus twitch and tetanic force generation and the rate of fatigue were evaluated during a 4-min period of repetitive stimulation. Although both hydralazine and amlodipine lowered blood pressure, they had different effects on muscle function. Hydralazine decreased force generation in both WKY and SHR at all stimulation frequencies; it did not change the fatigue properties of SHR but made WKY soleus less fatigue resistant. Amlodipine, on the other hand, increased contractile force in both WKY and SHR and increased fatigue resistance in SHR. Amlodipine is a dihydropyridine that blocks L-type channels, thereby preventing entry of Ca2+ into the muscle. We suggest that Ca2+ entry during activity stimulates Ca-activated K+ efflux in SHR and adds to the extracellular load of K+. Increased extracellular K+ can in turn depress contractile performance.

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amlodipine Norvasc
Comparison of effects of dihydropyridine calcium antagonists on left ventricular systolic and diastolic performance.

Cheng CP, Noda T, Nordlander M, Ohno M, Little WC.

Section of Cardiology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina.

We compared the effects of three dihydropyridine calcium antagonists (felodipine, nifedipine and amlodipine) on left ventricular (LV) contractile performance and diastolic filling dynamics in eight conscious animals. After administering metoprolol and atropine, felodipine (25 nmol/kg i.v.) produced significant decreases in LV end-systolic pressure (PES) (109 +/- 15 vs. 88 +/- 12 mmHg, P < .05) and arterial elastance (Ea) (12.6 +/- 4.5 vs. 8.5 +/- 3.4 mmHg/ml, P < .05), whereas the heart rate was unchanged. Felodipine increased the slopes of the end-systolic P-V relation (7.4 +/- 0.9 vs. 9.9 +/- 1.0 mmHg/ml, P < .05), the dP/dtmax-end diastolic volume (VED) relation (68.1 +/- 11.2 vs. 94.9 +/- 14.3 mmHg/sec/ml, P < .05), and the stroke work (SW)-VED relation (72.1 +/- 3.1 vs. 82.8 +/- 5.2 mmHg, P < .05), and shifted all three relations to the left, indicating enhanced contractile performance. In contrast, at doses that produced equivalent reductions of PES, nifedipine (375 nmol/kg i.v.) and amlodipine (780 nmol/kg i.v.), significantly decreased the slopes of the end-systolic P-V relation, the dP/dtmax-VED relation and the SW-VED relation and shifted all three relations to the right, indicating depressed LV contractile performance. Felodipine decreased the time constant (T) of LV relaxation (32.2 +/- 5.2 to 28.8 +/- 5.2 msec, P < .05) and increased the maximum rate of early diastolic LV filling (dV/dtmax) (167 +/- 22 to 207 +/- 26 ml/sec, P < .05). Amlodipine had the opposite effect, slowing T (31.0 +/- 4.9 to 33.9 +/- 5.4 msec, P < .05) and decreasing dV/dtmax (173 +/- 39 to 154 +/- 30 ml/sec, P < .05), whereas nifedipine had no significant effects on T, PGmax or dV/dtmax. Thus, we conclude that in conscious dogs after autonomic blockade, at dosages that produced equivalent arterial vasodilation, felodipine augmented, whereas amlodipine depressed, LV contractile performance, LV relaxation and early LV filling. Nifedipine decreased LV contractile performance but had no significant effect on LV relaxation and early LV filling.

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amlodipine Norvasc
Factors influencing isradipine and amlodipine binding to human plasma lipoproteins.

Oravcova J, Sojkova D, Fetkovska N, Trnovec T.

Department of Clinical Pharmacology, Institute of Preventive and Clinical Medicine, Bratislava, Slovak Republic.

The objectives of this study were to determine the distribution of isradipine among individual plasma lipoproteins ex vivo in healthy volunteers (n = 8) and in hypercholesterolaemic patients (n = 12), and to investigate the mechanisms involved in the interaction of isradipine and amlodipine with isolated lipoprotein fractions in vitro. The distribution study ex vivo demonstrated the different relative affinity of isradipine for the plasma lipoproteins: high-density lipoprotein (HDL) > low-density lipoprotein (LDL) > very low-density lipoprotein (VLDL). Isradipine binding correlated linearly with the cholesterol levels in LDL and VLDL; however, binding to HDL did not correlate with the cholesterol level in this fraction. The total binding affinity of isradipine to isolated LDL was markedly higher compared with amlodipine; total binding affinity (nKa) of isradipine vs amlodipine was (1.60 +/- 0.08) x 10(7) l/mol vs (4.14 +/- 0.33) x 10(6) l/mol, respectively. Binding to HDL was also higher with isradipine --nKa = (1.04 +/- 0.04) x 10(5) l/mol--compared with that of amlodipine: nKa = (3.82 +/- 0.18) x 10(4) l/mol. There was no significant competitive binding effect of cyclosporin A (CyA) on isradipine binding to individual lipoprotein fractions. It is likely that, in addition to the structure of surface apoproteins, the factors determining the interaction of calcium antagonists with plasma lipoproteins also include the plasma level of each lipoprotein fraction as well as the lipophilicity of the drug.

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amlodipine Norvasc
Differential effects of amlodipine and atorvastatin treatment and their combination on atherosclerosis in ApoE*3-Leiden transgenic mice.

Delsing DJ, Jukema JW, van de Wiel MA, Emeis JJ, van der Laarse A, Havekes LM, Princen HM.

Gaubius Laboratory, TNO-PG, Leiden, The Netherlands.

This study was designed to investigate the potential antiatherosclerotic effects of the calcium antagonist amlodipine as compared with the HMG-CoA reductase inhibitor atorvastatin and the combination of both in ApoE*3-Leiden transgenic mice. Four groups of 15 ApoE*3-Leiden mice were put on a high-cholesterol diet. One group received 0.002% (wt/wt) amlodipine in the diet, which had no effect on plasma cholesterol levels. Another group received 0.01% (wt/wt) atorvastatin, resulting in a decrease of plasma cholesterol by 50% by a reduction in very low density lipoprotein production. The combination group received both amlodipine and atorvastatin. After 28 weeks, atherosclerosis in the aortic root was quantified. Treatment with amlodipine had no significant effect on atherosclerotic lesion area, whereas atorvastatin markedly reduced atherosclerosis by 77% compared with the control group. Atorvastatin also reduced inflammation markers. The combination of amlodipine and atorvastatin tended to reduce lesion area by 61% compared with the atorvastatin-only group; however, this effect did not reach statistical significance. Amlodipine treatment significantly reduced calcification in the lesions, whereas atorvastatin alone had no effect. The combination of amlodipine and atorvastatin resulted in a near absence of calcium deposits in the lesions. This study demonstrates that amlodipine treatment alone does not significantly reduce atherosclerotic lesion development. Atorvastatin was shown to have strong antiatherosclerotic effects, and cotreatment with amlodipine may potentiate the antiatherosclerotic effect of atorvastatin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12827028&dopt=Abstract amlodipine Norvasc