Nonlinear pharmacokinetics of recombinant human macrophage colony-stimulating factor (M-CSF) in rats.
The pharmacokinetics and mechanisms of elimination of recombinant human macrophage-colony stimulating factor (M-CSF) were investigated in rats. Intravenous injections of 0.1, 1 or 10 mg/kg M-CSF were administered and plasma samples were measured for M-CSF by bioassay. Systemic clearance decreased and the shape of the concentration-time curve changed with increasing dose, indicating nonlinear pharmacokinetics. At 10 mg/kg, two half-lives were initially observed, but after about 20 hr the plasma M-CSF suddenly declined with a steep slope. The rapidly declining phase suggested a saturable clearance mechanism that was prominent at low plasma concentrations of M-CSF (below 300 ng/ml) and obscured at high plasma concentrations of M-CSF. The rapid decline of plasma M-CSF occurred at earlier times with multiple daily injections of M-CSF, indicating induction of the saturable clearance mechanism. The rapidly declining phase was inhibited by carrageenan, indicating that saturable clearance might be due to metabolism of M-CSF by macrophages. With ligation of either the renal pedicles or ureters, the apparent half-lives of M-CSF increased by a factor of 2- to 3-fold, while the occurrence of the rapidly declining phase was delayed, but not eliminated. Overall, the results are well described by a two-compartment, first-order elimination model with a parallel Michaelis-Menten elimination pathway. First-order elimination is largely performed by the kidneys and the saturable Michaelis-Menten elimination pathway appears to be mediated by cells of the monocyte-macrophage lineage.
Bauer
R J
RJ
Department of Pharmacology, Pharmacokinetics and Toxicology, Chiron Corporation, Emeryville, California.
Gibbons
J A
JA
Bell
D P
DP
Luo
Z P
ZP
Young
J D
JD
D000818:Animals; D016173:Macrophage Colony-Stimulating Factor / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics
D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor