PHARMACOKINETICS AND METABOLISM OF NILUTAMIDE IN THE ISOLATED RAT LUNG

Nilutamide (N) is a potent antiandrogen used in the treatment of diffuse carcinoma of the prostate. The drug has been implicated in a few instances of pneumonitis in man. The present studies were carried out to examine N disposition in the isolated perfused lung (IPL) from rats. Both recirculating and single-pass IPL were used. Recirculation was run for 60 min at concentrations of N ranging between 12 and 120-mu-M (+ 1-mu-Ci [C-14]N). Single-pass perfusions were run for 30 min (uptake, 10 min; efflux, 20 min) at inflowing concentrations ranging from 12 to 480-mu-M (+ 1-mu-Ci [C-14]N). Nilutamide was concentrated in the recirculating IPL, and tissue to medium ratio (T/M) ranged between 6.6 and 4.2, depending on the inflowing concentration of N (C(in)). High performance liquid chromatography analysis of extracts of 60-min lung homogenates demonstrated the primary amino metabolite of N in addition to the parent compound. This indicated reduction of the nitro moiety of N by lung tissues. At 60 min and C(in) = 40-mu-M, 17.6 +/- 4.7% of the radioactivity present in lung was accounted for by the metabolite. Perfusate samples contained low to undetectable amounts of the metabolite. No metabolism of N was detected in single-pass IPL, possibly because of the shorter duration of experiments. Amount of N taken up in lung and T/M were similar to those found in recirculating preparations. Uptake of N in the single-pass IPL was proportional to N concentration up to 480-mu-M. Female IPL accumulated N to an extent comparable to that of males. The magnitude of N uptake was not influenced by coperfusion of N and amiodarone (90-mu-M), chlorphentermine (90-mu-M), iodoacetate (1 mM), nitrofurantoin (90-mu-M), ouabain (1 mM), paraquat (90-mu-M or 1 mM), spermidine (90-mu-M), taurine (90-mu-M), testosterone (90-mu-M) or ice-cold or Na+-free medium. Efflux in single-pass IPL showed that N was not avidly sequestered in lung. These results indicate that in the rat IPL, 1) N accumulates mostly by diffusion and binding, 2) N uptake is not influenced by coadministration of inhibitors or pneumotropic drugs and 3) N undergoes reductive metabolism to its amino derivative.