Felodipine pharmacokinetics and molecular data

Pharmacokinetics
Mechanism Oral administration Intravenous administration Oral administration (extended release) Young/healthy volunteers Excretion Hypertensive patients Bioavailability Geriatric use Hepatic dysfunction Cardiovascular effects Renal/endocrine effects
 * Overview
 * In vitro studies
 * Blood pressure/diuretic effect

Overview
Felodipine is a member of the dihydropyridine class of calcium channel antagonists (calcium channel blockers). It reversibly competes with nitrendipine and/or other calcium channel blockers for dihydropyridine binding sites, blocks voltage-dependent Ca++ currents in vascular smooth muscle and cultured rabbit atrial cells, and blocks potassium-induced contracture of the rat portal vein. Return to top

In vitro studies
In vitro studies show that the effects of Felodipine on contractile processes are selective, with greater effects on vascular smooth muscle than cardiac muscle. Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals. Return to top

Blood pressure/diuretic effect
The effect of Felodipine on blood pressure is principally a consequence of a dose-related decrease of peripheral vascular resistance in man, with a modest reflex increase in heart rate (see Cardiovascular Effects). With the exception of a mild diuretic effect seen in several animal species and man, the effects of Felodipine are accounted for by its effects on peripheral vascular resistance. Return to top

Oral administration
Following oral administration, Felodipine is almost completely absorbed and undergoes extensive first-pass metabolism. The systemic bioavailability of Felodipine is approximately 20%. Mean peak concentrations following the administration of Felodipine are reached in 2.5 to 5 hours. Both peak plasma concentration and the area under the plasma concentration time curve (AUC) increase linearly with doses up to 20 mg. Felodipine is greater than 99% bound to plasma proteins. Return to top

Intravenous administration
Following intravenous administration, the plasma concentration of Felodipine declined triexponentially with mean disposition half-lives of 4.8 minutes, 1.5 hours, and 9.1 hours. The mean contributions of the three individual phases to the overall AUC were 15, 40, and 45%, respectively, in the order of increasing t1/2. Return to top

Oral administration (extended release)
Following oral administration of the immediate-release formulation, the plasma level of Felodipine also declined polyexponentially with a mean terminal t1/2 of 11 to 16 hours. The mean peak and trough steady-state plasma concentrations achieved after 10 mg of the immediate-release formulation given once a day to normal volunteers, were 20 and 0.5 nmol/L, respectively. The trough plasma concentration of Felodipine in most individuals was substantially below the concentration needed to effect a half-maximal decline in blood pressure (EC50) [4-6 nmol/L for Felodipine], thus precluding once-a-day dosing with the immediate-release formulation. Return to top

Young/healthy volunteers
Following administration of a 10-mg dose of Felodipine, the extended-release formulation, to young, healthy volunteers, mean peak and trough steady-state plasma concentrations of Felodipine were 7 and 2 nmol/L, respectively. Corresponding values in hypertensive patients (mean age 64) after a 20-mg dose of Felodipine were 23 and 7 nmol/L. Since the EC50 for Felodipine is 4 to 6 nmol/L, a 5- to 10-mg dose of Felodipine in some patients, and a 20-mg dose in others, would be expected to provide an antihypertensive effect that persists for 24 hours. The systemic plasma clearance of Felodipine in young healthy subjects is about 0.8 L/min, and the apparent volume of distribution is about 10 L/kg. Return to top

Excretion
Following an oral or intravenous dose of 14C-labeled Felodipine in man, about 70% of the dose of radioactivity was recovered in urine and 10% in the feces. A negligible amount of intact Felodipine is recovered in the urine and feces (< 0.5%). Six metabolites, which account for 23% of the oral dose, have been identified; none has significant vasodilating activity. Return to top

Hypertensive patients
Following administration of Felodipine to hypertensive patients, mean peak plasma concentrations at steady state are about 20% higher than after a single dose. Blood pressure response is correlated with plasma concentrations of Felodipine. Return to top

Bioavailability
The bioavailability of Felodipine is influenced by the presence of food. When administered either with a high fat or carbohydrate diet, Cmax is increased by approximately 60%; AUC is unchanged. When Felodipine was administered after a light meal (orange juice, toast, and cereal), however, there is no effect on Felodipine's pharmacokinetics. The bioavailability of Felodipine was increased approximately two-fold when taken with grapefruit juice. Orange juice does not appear to modify the kinetics of Felodipine. A similar finding has been seen with other dihydropyridine calcium antagonists, but to a lesser extent than that seen with Felodipine. Return to top

Geriatric use
Plasma concentrations of Felodipine, after a single dose and at steady state, increase with age. Mean clearance of Felodipine in elderly hypertensives (mean age 74) was only 45% of that of young volunteers (mean age 26). At steady state mean AUC for young patients was 39% of that for the elderly. Data for intermediate age ranges suggest that the AUCs fall between the extremes of the young and the elderly. Return to top

Hepatic dysfunction
In patients with hepatic disease, the clearance of Felodipine was reduced to about 60% of that seen in normal young volunteers. Renal impairment does not alter the plasma concentration profile of Felodipine; although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. Animal studies have demonstrated that Felodipine crosses the blood-brain barrier and the placenta. Return to top

Cardiovascular effects
Following administration of Felodipine, a reduction in blood pressure generally occurs within 2 to 5 hours. During chronic administration, substantial blood pressure control lasts for 24 hours, with trough reductions in diastolic blood pressure approximately 40-50% of peak reductions. The antihypertensive effect is dose dependent and correlates with the plasma concentration of Felodipine. A reflex increase in heart rate frequently occurs during the first week of therapy; this increase attenuates over time. Heart rate increases of 5-10 beats per minute may be seen during chronic dosing. The increase is inhibited by beta-blocking agents. The P-R interval of the ECG is not affected by Felodipine when administered alone or in combination with a beta-blocking agent. Felodipine alone or in combination with a beta-blocking agent has been shown, in clinical and electrophysiologic studies, to have no significant effect on cardiac conduction (P-R, P-Q, and H-V intervals). In clinical trials in hypertensive patients without clinical evidence of left ventricular dysfunction, no symptoms suggestive of a negative inotropic effect were noted; however, none would be expected in this population. Return to top

Renal/endocrine effects
Renal vascular resistance is decreased by Felodipine while glomerular filtration rate remains unchanged. Mild diuresis, natriuresis, and kaliuresis have been observed during the first week of therapy. No significant effects on serum electrolytes were observed during short- and long-term therapy. In clinical trials in patients with hypertension, increases in plasma noradrenaline levels have been observed. Return to top