Pulmonary absorption of recombinant methionyl human granulocyte colony stimulating factor (r-huG-CSF) after intratracheal instillation to the hamster.

Abstract

Recombinant methionyl human granulocyte colony stimulating factor (G-CSF), a molecule of 18.8 kDa, has been shown to induce a systemic response after delivery by aerosol. In this work, rate and extent of absorption as well as the response were determined after bolus administration of solutions by intratracheal instillation (IT). The protein was quantified using a specific ELISA and the biological response was assessed by monitoring the increase in numbers of circulating white blood cells (WBC). A dose-response curve was obtained after IT, subcutaneous injection (SC), and intracardiac injection (IC) of 100 microL of a nominal dose ranging from 1 to 1000 micrograms/kg G-CSF (n = 5). WBC numbers were determined 24 hr postadministration. Absorption and clearance kinetics were determined after IT and IC of 500 micrograms/kg protein over a 24-hr time period (n = 5). The response of the lung to G-CSF was monitored by WBC counts and differentials in lung lavage fluid. 73.6 +/- 10.5% (n = 7) of the IT dose reached the lung lobes. The response to single doses of G-CSF by IT or SC was similar, with WBC numbers increasing over 4x baseline at the higher doses. Absorption from the lung was rapid and did not follow first-order kinetics. Clearance after the IC dose was described by a biexponential equation (alpha = 1.41, beta = 0.24 hr-1). Peak serum levels were obtained approximately 1-2 hr after IT. The bioavailability was 45.9% of the administered dose and 62.0% of the dose reaching the lung lobes. These results indicate that G-CSF is rapidly absorbed from the lung.(ABSTRACT TRUNCATED AT 250 WORDS)