Pharmacokinetics of high-dose recombinant erythropoietin in plasma and brain of neonatal rats.
Recombinant human erythropoietin (rEpo) is neuroprotective in neonatal models of brain injury. Pharmacokinetic data regarding the penetration of circulating rEpo into brain tissue is needed to optimize neuroprotective strategies. We sought to determine the pharmacokinetics of rEpo given intraperitoneally or subcutaneously in plasma and brain. We hypothesized that 1) exogenous rEpo would penetrate the blood-brain barrier (BBB), 2) brain and plasma Epo would correlate, and 3) brain injury would enhance rEpo penetration. Two hundred and eighty-four 7-d-old control, sham, or brain-injured rats were treated with i.p. or s.c. rEpo (0, 250, 2500, or 5000 U/kg) and killed at scheduled intervals. Plasma and brain tissue were collected. Epo concentrations were measured by ELISA. Intraperitoneal injection yielded a faster and greater peak concentration of plasma rEpo (Tmax 3 h, Cmax 10,016 +/- 685 mU/mL) than s.c. injection (Tmax 9 h, Cmax 6224 +/- 753 mU/mL). Endogenous brain Epo was below detection even after hypoxia exposure. Systemic rEpo crossed the BBB in a dose-dependent manner, peaked in brain at 10 h, and was increased after brain injury. We conclude that high-dose rEpo is detectable in brain for >20 h after a single systemic injection. These pharmacokinetic data are valuable for planning of rEpo neuroprotection experiments.
Statler
Pamela A
PA
Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA.
McPherson
Ronald J
RJ
Bauer
Larry A
LA
Kellert
Brian A
BA
Juul
Sandra E
SE
D000818:Animals; D001921:Brain / Q000378:metabolism*; D004921:Erythropoietin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins
D011994:Recombinant Proteins; D004921:Erythropoietin