Amlodipine pharmacokinetics

The effect of sildenafil on arterial pressure has been tested in 16 hypertensive men taking amlodipine 5-10 mg/day (23). Sildenafil did not affect amlodipine pharmacokinetics, but caused a further additive fall in blood pressure. Adverse events with the combination of sildenafil and amlodipine, headache, dyspepsia, and nausea, did not require drug withdrawal. 

Quoted as unpublished data, Pfizer Central Research by Abemetlty DR. Amlodipine pharmacokinetic profile of a low-clearance calcium antagonist J Cardiovasc Pharmacol (1991)... 

Amlodipine — Ma et al.50 developed and validated a UPLC/MS/MS method for a pharmacokinetic study of amlodipine in human plasma after oral administration. Nimodipine 50 fig/mL in a mixture of methanol and water (50 50 v/v) served as the IS. Standard solutions of amlodipine were also prepared in a mixture of methanol and water (50 50 v/v). 

Ma, Y. et al. 2007. Determination and pharmacokinetic study of amlodipine in human plasma by ultra performance liquid chromatography-electrospray ionization mass spectrometry. J Pharm Biomed Anal. 43 1540. 

The pharmacokinetics of several drugs that are known P-gp substrates were not altered by GFJ in several clinical studies that investigated the effect of GFJ on the bioavailability of digoxin, amlodipine, and indinavir (27,75,99). Possible other unknown mechanisms and factors such as strength of the administered juices and length of consumption are relevant for the interactions of citrus with drugs (100). 

Josefsson M, Zackrisson AL, Ahlner J. Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers. Eur J Clin Pharmacol 1996 51(2) 189-193. 

Vincent J, Harris SI, Foulds G, Dogolo LC, Willavize S, Friedman HL. Lack of effect of grapefruit juiee on the pharmacokinetics and pharmacodynamics of amlodipine. Br J Clin Pharmacol 2000 50(5) 455-463. 

The pharmacokinetic properties of these drugs are set forth in Table 12-5. The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties. Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities. A combination of verapamil or diltiazem with 3 blockers may produce atrioventricular block and depression of ventricular function. In the presence of overt heart failure, all calcium channel blockers can cause further worsening of heart failure as a result of their negative inotropic effect. Amlodipine, however, does not increase the mortality of patients with heart failure due to nonischemic left ventricular systolic dysfunction and can be used safely in these patients. 

Kuzuya T, Kobayashi T, Moriyama N, Nagasaka T, Yokoyama I, Uchida K, Nakao A, Nabeshima T. Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients. Transplantation 2003 76 865-868. 

The non-specific interaction of amlodipine with the membrane may thus lead to a defined and specific location, orientation, and conformation required for binding to a transmembrane receptor protein. It may help to understand and explain its pharmacodynamic and pharmacokinetic profile, which shows a slow onset and a long duration of activity compared with uncharged drugs of this class [95]. 

Other sex-related differences in cardiovascular effect include the finding that antihypertensive drugs such as amlodipine exhibit greater antihypertensive effects in women than in men (119). Whether this greater response is due to differences in pharmacokinetics or pharmacodynamics is difficult to determine. Better blood pressure control could be explained by higher plasma drug concentrations in women, but pharmacokinetic differences do not necessarily correlate with the pharmacodynamic effects of antihypertensive drugs. 

However, some calcium channel blockers have pharmacokinetic interactions diltiazem, verapamil, nicardipine, and amlodipine increase ciclosporin concentrations, whereas nifedipine, felodipine, and isradipine do not (SED-14, 604) (SEDA-21, 210) (SEDA-21, 212)... 

Yeung, P.K.F. Mosher, S.J. Poliak, P.T. Liquid chromatography assay for amlodipine chemical stability and pharmacokinetics in rabbits. J.Pharm.Biomed.Anal., 1991, 9, 565-571... 

Walker, D.K. Humphrey, M.J. Smith, D.A. Importance of metaboUc stabiUty and hepatic distrihution to the pharmacokinetic profile of amlodipine. Xenobiotica, 1994, 24, 243-250... 

Several studies have raised concerns about the long-term safety of short-acting nifedipine. The proposed mechanism for this adverse effect lies in abrupt vasodilation with reflex sympathetic activation. There does not appear to be either significant reflex tachycardia or long-term adverse outcomes from treatment with sustained-release forms of nifedipine or with dihydropyiidine Ca blockers such as amlodipine or felodipine, which have more favorable (slower) pharmacokinetics. 

The calcium channel blockers are rapidly and completely absorbed after oral administration (see Table 28.11 for summary of pharmacokinetic parameters). Prehepatic first-pass metabolism by CYP3A4 enzymes occurs with some orally administered calcium channel blockers, especially verapamil, with its low bioavailability of 20 to 35%. The bioavailability of diltiazem is 40 to 67%, of nicardipine 35%, of nifedipine 45 to 70%, and of amlodipine 64 to 90%. Verapamil is metabolized by CYP3A4 N-demethylation to its principal metabolite, norverapamil, which retains approximately 20% of the activity of verapamil, and by 0-demethylation (CYP2D6) into inactive metabolites. Diltiazem is metabolized by enzyme hydrolysis to its primary metabolite, desacetyl derivative, which retains approximately 25 to 50% of the activity of diltiazem. The oral bioavailability of diltiazem and verapamil may be increased with chronic use and increasing dose (i.e., bioavailability is nonlinear). Diltiazem undergoes ... 

A study in 12 healthy subjects indicated that there was no pharmacokinetic interaction between single doses of amlodipine 5 mg and benazepril 10 mg. ... 

Sun JX, Cipriano Chan K, John VA. Pharmacokinetic interaction study between benazepril and amlodipine in healtiiy subjects. EurJ Clin Pharmacol (1994) 47,285-9. 

No significant pharmacokinetic interactions occur between nifedipine and candesartan or irbesartan, or between amlodipine and telmisartan or valsartan. Calcium-channel blockers have been given safely with eprosartan or irbesartan. 

In a study in 12 healthy subjects, telmisartan 120 mg daily had no clinically relevant effect on the pharmacokinetics of amlodipine 10 mg daily for 9 days, and there was no evidence of any marked effect of amlodipine on the pharmacokinetics of telmisartan. Although there were no serious adverse effects, mild to moderate adverse events (most commonly headache) occurred slightly more frequently with the comhination, compared with amlodipine alone (19 events versus 12 events). ... 

In 12 healthy subjects the pharmacokinetics of single oral doses of valsartan 160 mg and amlodipine 5 mg were not significantly altered on concurrent use, although the pharmacokinetics of valsartan showed wide variations between subjects. ... 

Slangier J, Su C-APF. Pharmacokinetics of repeated oral doses of amlodipine and amlodipine plus telmisartan in healthy volunteers. J Clin Pharmacol (2000) 40,1347-54. 

A study in 30 healthy subjects found that single and multiple doses of amlodipine 10 mg for 15 days (with or without lisinopril and simvastatin) had no effect on the pharmacokinetics of alcohol 0.8 g/kg nor on subjective psychological performance. Alcohol did not alter the pharmacokinetics of amlodipine. ... 

Although information is limited, these pharmacokinetic interactions are predictable, and potentially serious. To date, clinically relevant increases in calcium-channel blocker levels or effects have been shown for nelfinavir with nifedipine or felodipine, indinavir/ritonavir with amlodipine, diltiazem or nifedipine, and atazanavir with diltiazem. Caution would be required with any of these combinations, anticipating the need to use lower doses of the calcium-channel blocker. The manufacturers specifically recommend that if diltiazem is given with atazanavir the initial dose of diltiazem should be reduced by 50% with subsequent dose titration and ECG monitoring. They also note that verapamil levels may be raised and therefore advise caution. Similarly, the manufaeturers of nifedipine say that blood pressure monitoring is required and a reduction in nifedipine dose may be neeessary if it is given with HIV-protease inhibitors. However, some UK manufacturers (e.g. felodipine, lercanidipine, nimodipine ) recommend avoiding the concurrent use of ritonavir and other protease inhibitors if possible. 

The manufacturers of amlodipine state that it does not affect the pharmacokinetics of atorvastatin. They also note that no clinically significant interactions were seen in clinical studies in which atorvastatin was used with antihypertensives, including unspecified calcium-channel blockers. However, they do warn that drugs that are metabolised by the cytochrome P450 isoenzyme CYP3A4 (e.g. calcium-channel blockers) do have the potential to interact. ... 

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