Distribution, metabolism, and excretion of a novel surface-active agent, purified poloxamer 188, in rats, dogs, and humans.
Purified poloxamer 188 (PP188) is a nonionic, block copolymer surfactant with hemorheologic, antithrombotic, and anti-adhesive properties. PP188 is being studied in phase III clinical trials in sickle cell disease and has been found to be well tolerated and has demonstrated benefit in ameliorating the effects of acute painful vasoocclusive crisis. The disposition of PP188 was studied in rats, dogs, and humans to establish a basis for understanding the safety parameters in support of clinical trials. PP188 was primarily distributed in extracellular water with little or no uptake by red blood cells, and had its highest concentrations in highly perfused tissues such as the kidney, liver, spleen, lymph nodes, and gastrointestinal tract. PP188 had no apparent effect on P450 isozymes in vitro. Metabolism was limited (< 5% of dose) with a higher molecular weight copolymer being the only other material detected in plasma or urine. Renal clearance was the controlling route of clearance for PP188 from the body. The 48-h intravenous infusion doses of PP188 were cleared in all species by approximately 1 week after the cessation of dose administration. PP188's disposition is a model for other nonionic block copolymers with similar physical and chemical properties.
Grindel
J Michael
JM
CytRx Corporation, 154 Technology Parkway, Suite 200, Norcross, Georgia 30092, USA. grindelm@cytrx.com
Jaworski
Ted
T
Piraner
Olga
O
Emanuele
R Martin
RM
Balasubramanian
M
M
D000818:Animals; D002250:Carbon Radioisotopes; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020442:Poloxamer / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013501:Surface-Active Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D065607:Cytochrome P-450 Enzyme Inhibitors; D013501:Surface-Active Agents; D020442:Poloxamer