Pharmacokinetics and Distribution of Recombinant Secretory Leukocyte Proteinase Inhibitor in Rats

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Abstract
Secretory leukocyte proteinase inhibitor (SLPI) is a potent elastase, trypsin, and chymotrypsin inhibitor occurring in all mucous secretions. Its inhibitory potency and profile suggested that it may become a therapeutic adjuvant in dsieases where proteinases play a pathogenetic role. In the course of developing recombinant SLPI for therapeutic purposes, we studied its pharmacokinetics after intravenous, intraperitoneal, and intratracheal application to rats. In plasma, SLPI was determined with an ELISA or by following a radiotracer ([35S]SLPI). In bronchoalveolar lavage fluid (BALF), SLPI was determined additionally by a functional assay (elasase inhibitory capacity). Intravenously applied SLPI (2 mg/kg) was rapidly cleared, with half-times of distribution of 6 min and half-times of elimination of 50 min. Very little (< 5%) appeared in the urine even after 24 h. Approximately 80% of intraperitoneally injected SLPI (12 mg/kg) was absorbed and generated maximal plasma concentration of 6 to 10 .mu.g/ml 30 to 120 min after administration. When given intratracheally (8.6 mg/kg), SLPI disappeared from the lungs, with a half-time of 4 to 5 h. This value was the same whether the remaining SLPI in BALF was determined radiometrically, by ELISA or by the functional assay, indicating minimal metabolism in the lung. As in the case of intraperitoneal application, SLPI was absorbed systematically, resulting in a maximal plasma level of about 2 .mu.g/ml 1 to 2 h after application. In contrast to the measurements in BALF, the ELISA and radiotracer measurements in plasma correlated only for the first 2 h after application and diverged progressively after that, suggesting breakdown of the molecule once it reaches the plasma. The data provided demonstrate that in the rat, intratracheally applied SLPI remains in the lung in active form for several hours and may thus provide effective protection against proteinase-mediated lung damage.