Pharmacokinetics of amiodarone in the isolated rat lung.

In these studies we examined the kinetics of amiodarone (Am) uptake and efflux in/from the lung, and the influence of other amphiphilics on these processes. We used single-pass perfused isolated lungs from rats. Medium containing Am (30 microM + 1 microCi of [14C]Am) was perfused through the lung for 20 min (uptake), followed by 20 min of perfusion with drug-free medium (efflux). Lack of metabolism enabled us to follow Am by measuring the amount of radioactivity in perfusate and lung. Other concentrations of Am (3, 60 and 120 microM; n = 2-4 each) were also examined. Inhibited uptake and accelerated efflux of Am were attempted with the pneumophilic amphiphilics chlorimipramine, chlorphentermine, chlorpromazine, verapamil and with the main metabolite of Am: desethylamiodarone (60 and/or 240 microM; n = 3-4 lungs each). Lung extracted Am extensively during uptake. The amount of Am accumulated at 20 min (inflowing concentration: 30 microM) averaged 1307 +/- 109 (S.E.) nmol/g, corresponding to a tissue to medium ratio of 43.3 +/- 1.6. Spontaneous efflux of Am was incomplete. At 40 min, 862 +/- 105 nmol of Am remained bound per g of lung, suggesting sequestration of Am in a slowly effluxable pool in which calculations show that more than 50% of the drug will ultimately persist. Uptake and efflux rates obey biexponential kinetics, indicating storage into two pools. Uptake rate and the amount of Am accumulated in lung at 20 min increased in proportion to inflowing concentration up to 60 microM. At 120 microM the increase was less. Neither amphiphilic was capable of inhibiting Am uptake, whereas only chlorphentermine significantly accelerated Am efflux.(ABSTRACT TRUNCATED AT 250 WORDS)