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 microM (+1 mu Ci [14C]N). Single-pass perfusions were run for 30 min (uptake, 10 min; efflux, 20 min) at inflowing concentrations ranging from 12 to 480 microM (+1 mu Ci [14C]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 (Cin). 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 Cin = 40 microM, 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 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
Camus
P
P
Unit of Pulmonary Pharmacology and Toxicology, Université de Bourgogne, Dijon, France.
Coudert
B
B
D'Athis
P
P
Foucher
P
P
Delchambre
J
J
Dupront
A
A
Jeannin
L
L
D000726:Androgen Antagonists / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D048289:Imidazolidines; D008168:Lung / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
D000726:Androgen Antagonists; D007093:Imidazoles; D048289:Imidazolidines; C021277:nilutamide