Felodipine kinetics in healthy men

Abstract

In a randomized, crossover study, the absorption, distribution, and elimination of intravenous and oral felodipine were investigated in eight healthy men 22 to 31 years old. Felodipine was given as a 2.5 mg iv infusion over 30 minutes and as a 27.5 mg oral solution. Both doses were labeled with 25 microCi 14C-felodipine. Given as an oral solution, felodipine is rapidly (mean time to peak concentration 64 minutes; range 30 to 90 minutes) and completely absorbed. Presystemic elimination reduced the availability to 16% (range 10% to 25%). Felodipine kinetics can be described by a multicompartmental model with three distinct phases. The t1/2 for the initial phase was 6.4 minutes (range 1.7 to 10.4 minutes) and felodipine was distributed to a volume of 0.6 L/kg (range 0.4 to 0.9 L/kg), which approximately corresponds to the total body water. The second distribution phase reached pseudoequilibrium with a t1/2 of 1.6 hours (range 1.3 to 2.2 hours). The volume of distribution at the end of this phase was 9.7 L/kg (range 6.0 to 18.2 L/kg). The terminal phase had t1/2 of 10.2 hours (range 6.7 to 20.7 hours). The contribution of the three phases to the AUC was 15%, 40%, and 45% in the order of increased t1/2. Total body clearance of felodipine was 1.2 L/min (range 0.9 to 1.6 L/min). Within 72 hours after drug dosing, 62% to 81% of the felodipine doses were excreted in the urine and feces as metabolites. The rate of excretion by the kidneys had a biphasic pattern, with t1/2 values of 4 and 18 hours. Approximately 10% of the doses was excreted in the feces.

Pharmacokinetics of felodipine in patients with impaired renal function.

“…The method measures concentrations down to 0.5 nmol l-1 with a coefficient of variation of 15%. Total radioactivity in plasma and urine was measured by liquid scintillation counting (Edgar et al, 1985b).…”

“…The glomerular filtration rate (GFR), measured by this method, ranged between 8 and 68 ml min-' (Table 1), and plasma creatinine varied from 143 to 546 ,umol I-1. The pharmacokinetic data from this study were compared with those from a group of eight healthy subjects (Edgar et al, 1985b), where plasma creatinine varied between 92 and 125 ,umol 1-1.…”

“…Observed differences were accepted as statistically significant at a probability level of P < 0.05. The values of the parameters obtained in this study were compared with those from a study in healthy subjects (Edgar et al, 1985b) using the Mann-Whitney test.…”

“…The primary metabolite is further metabolised by cleavage of the methyl and ethyl esters and by oxidation of the methyl groups to the corresponding acids and alcohols. (Hoffman & Andersson, 1987) Less than 0.5% of a given dose is excreted in unchanged form and as H152/37 in the human urine (Edgar et al, 1985b). However, the kidneys play an important role in the elimination of the secondary metabolites as about 70% of a 14C-labelled i.v.…”

“…The pharmacokinetics of felodipine have previously been described in young healthy subjects and in patients with primary hypertension (Edgar et al, 1985b(Edgar et al, , 1987a following single dose administration. These studies have shown that felodipine is a high clearance drug extensively bound to plasma proteins.…”