Changes in erythropoietin pharmacokinetics following busulfan-induced bone marrow ablation in sheep: evidence for bone marrow as a major erythropoietin elimination pathway.
The contribution of the bone marrow to in vivo erythropoietin (EPO) elimination was evaluated by determining EPO pharmacokinetic (PK) parameters in five adult sheep in a paired manner before and after chemotherapy-induced marrow ablation. After busulfan-induced bone marrow ablation, EPO PK demonstrated progressive decreases in plasma clearance (CL), elimination half-life [t1/2(beta)], and volume of distribution at steady state (Vss) with concomitant increases in mean residence time (MRT). Eight days after beginning busulfan treatment, there were no further changes in CL, t1/2(beta), MRT, and Vss. Only 20% of baseline CL remained by day 8. The volume of distribution (Vc) and distribution half-life [t1/2(alpha)], in contrast, remained unchanged from baseline. White blood cell counts and reticulocytes gradually declined after the start of marrow ablation. Examination of bone marrow core biopsy samples obtained on day 10 revealed less than 10% of baseline marrow cellularity. No colony-forming unit erythroid (CFU-E) colonies were found after 6 days of incubation for bone marrow aspirates drawn at days 8 and 13 following busulfan treatment, whereas pre-busulfan aspirates yielded 29 CFU-E colonies per 10(5) cells in CFU-E cultures. Treatment of a sheep with 5-fluorouracil showed changes in PK parameters that were similar to the results from treatment with busulfan. The present study indicates that the bone marrow significantly contributes to the elimination of EPO in vivo.
Chapel
S
S
The Colleges of Pharmacy, Department of Pediatrics, The University of Iowa, Iowa City, Iowa 52242, USA.
Veng-Pedersen
P
P
Hohl
R J
RJ
Schmidt
R L
RL
McGuire
E M
EM
Widness
J A
JA
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002066:Busulfan / Q000494:pharmacology*; D004921:Erythropoietin / Q000493:pharmacokinetics*; D005472:Fluorouracil / Q000494:pharmacology; D006207:Half-Life; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D012756:Sheep
D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D004921:Erythropoietin; D002066:Busulfan; D005472:Fluorouracil