[Clinical pharmacokinetics of almitrine dimesylate]

In healthy subjects, almitrine bismesylate taken orally as tablets is rapidly absorbed from the digestive tract, with an overall bioavailability of about 70%. Drug kinetics are linear and independent of route of administration and therapeutic doses. Protein binding is approximately 99%, irrespective of plasma concentrations. Wide diffusion through body tissues is reflected in the apparent volume of distribution approaching 15 l/kg. In all animal species studied, almitrine is primarily metabolized in the liver. Its main metabolites are the tetrahydroxyl, mono-deallyl, di-deallyl and detriazinyl derivatives, all devoid of pharmacological activity and excreted mostly through the bile. Plasma elimination half-life varies from 45 to 50 hours. Plasma clearance (4 ml/min/kg) is about the same as hepatic clearance. As compared with healthy subjects, the pharmacokinetic values of almitrine bismesylate are identical in patients with chronic respiratory failure and not significantly different (notably with regard plasma clearance) in patients with renal impairment. However, absorption may be normal, reduced or delayed in patients with impaired liver functions, resulting in more variable values. Following repeated administration of the drug to healthy volunteers, steady state is reached in about 15 days. In chronic obstructive lung disease, long-term oral administration of almitrine bismesylate 100 mg/day divided into two 50 mg doses results in plasma concentrations that are 2 to 3 times higher than after one single 100 mg dose.