QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.063289v1 309/3/1085    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Segrave, A. M. Articles by Porter, C. J. H. Search for Related Content PubMed PubMed Citation Articles by Segrave, A. M. Articles by Porter, C. J. H.

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics of Recombinant Human Leukemia Inhibitory Factor in Sheep

Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia (A.M.S., S.A.C., C.J.H.P.); National Institute on Aging, National Institutes of Health, Gerontology Research Center, Baltimore, Maryland (D.E.M.); and Department of Veterinary Sciences, University of Melbourne, Werribee, Victoria, Australia (G.A.E.)

The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 µg/kg rhLIF (n = 2) or s.c. doses of 10, 20, or 50 µg/kg rhLIF (n = 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Noncompartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF. The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration.

Address correspondence to: Dr. Susan A. Charman, Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. E-mail: susan.charman{at}vcp.monash.edu.au