Abstract
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.
Footnotes
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↵1 These authors contributed equally to this publication.
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This work was funded by Amrad Corporation Limited and the Intramural Research Program of the National Institute on Aging.
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DOI: 10.1124/jpet.103.063289.
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ABBREVIATIONS: LIF, leukemia inhibitory factor; AUC, total area under the plasma drug concentration-time curve; ELISA, enzyme-linked immunosorbent assay; rhLIF, recombinant human LIF.
- Received November 21, 2003.
- Accepted February 2, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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