Affiliation:
1. Gilead Sciences Inc., Foster City, California 94404, USA.
Abstract
GS4071 is a novel potent inhibitor of influenza neuraminidase (Ki < 1 nM) with low (< 5%) oral bioavailability in animals. An ethyl ester prodrug of GS4071, GS4104, has exhibited good oral bioavailability in rat, mouse, and dog models and is currently being developed for the treatment of influenza A and B virus infections. Since influenza virus replicates primarily in the surface epithelial cells of the respiratory tract, the ability of the prodrug to deliver GS4071 to the bronchoalveolar lining fluid (BALF) following an oral dose of GS4104 should be an important indicator of its potential efficacy. In the present study, we determined the concentration-time profiles of GS4071 in the BALF and plasma of rats following oral administration of GS4104. The BALF was sampled by bronchoalveolar lavage with endogenous urea as a dilution marker. The concentration of GS4071 in BALF reached a peak at 2 h (1 h after the plasma peak) and declined at a slower rate than plasma levels, suggesting slow clearance of drug from the lung acini. The ratios of the area-under-the-curve (AUC) values of GS4071 in BALF to those in plasma were 1.05 for AUC from 0 to 6 h (AUC(0-6)) and 1.51 for AUC(0-infinity), indicating significant penetration of the parent drug into the lower respiratory tracts of rats following oral administration of the prodrug. No unchanged GS4104 was detected in BALF.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference14 articles.
1. The pulmonary uptake, accumulation and metabolism of xenobiotics. Annu;Bend J. R.;Rev. Pharmacol. Toxicol.,1985
2. Bergogne-Berezin E. 1988. Pharmacokinetics of antibiotics in respiratory secretions p. 608-631. In J. E. Pennington (ed.) Respiratory infections: diagnosis and management. Raven Press New York N.Y.
3. The localization, metabolism and effects of drugs and toxicants in Iung;Brown E. A. B.;Drug Metab. Rev.,1974
4. Kim C. U. W. Lew M. Williams L. Zhang S. Swaminathan N. Bischofberger M. S. Chen D. Mendel W. Li L. Tai P. Escarpe K. C. Cundy E. J. Eisenberg S. Lacy R. W. Sidwell R. C. Stevens and W. G. Laver. 1996. New potent orally active neuraminidase inhibitors as anti-influenza agents: in vitro and in vivo activity of GS4071 and analogs abstr. H-44 p. 171. In Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology Washington D.C.
5. Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution;Rennard S.;J. Appl. Physiol.,1986
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