The pharmacokinetics and metabolism of almitrine bismesylate.

Almitrine Bismesylate (ABM) is a highly lipophillic compound of molecular weight 669.7, under development as a peripheral chemoreceptor stimulant in the treatment of chronic bronchitis and emphysema. Its pharmacokinetics and metabolism were investigated in animals and man. Following oral administration of [14C]-ABM, absorption of radioactivity is rapid and variable in man, rat, rabbit and dog. Plasma levels of radioactivity decline rapidly after both oral and intravenous administration, suggesting rapid uptake into tissues. A high affinity of almitrine for the carotid body of the urethane-anaesthetised rat confirms a prolonged and specific action of the compound. Elimination of radioactivity is slow and mainly faecal and independent of administration route or species. Recovery of the adminstered radioactivity is incomplete in all other species except rat and in man, only 86 to 94% of the administered dose was recovered in 140 days. This slow elimination may be due to repeated gut secretion and reabsorption of almitrine. Almitrine is metabolised by oxidation and N-dealkylation of the allyl side chain to form, respectively, the di- and tetrahydroxy almitrine and mono and di-deallyl almitrine with the corresponding dihydroxy monodeallyl almitrine. The major faecal metabolite in all species is tetrahydroxy almitrine (not found in plasma) and all species had qualitatively similar metabolic patterns to man both in-vivo and in-vitro from liver microsomes. The pharmacokinetics of unchanged almitrine in man shows a rapid absorption from both solution and tablet formulations. Absorption is increased (48%) in the presence of food and bioavailability is high (74%). A large volume of distribution (3100 litres) and low clearance (64ml.min-1) are consistent with a long half-life (614 to 1164h). Plasma protein binding is high (99%) in all species and is not affected by drugs likely to be coadministered with almitrine. Clinically, there is a relationship between almitrine plasma concentration and changes in Pa02 from baseline during repeated administration. Some patients with high plasma levels of almitrine (>300ng.ml-1) experienced peripheral paresthesia which is reversible. Using simulations, dosage adjustments have shown that it is possible to maintain therapeutic levels of almitrine without side effects.