Dose-dependent hyperlipidemia in rabbits following administration of poloxamer 407 gel.
Poloxamer 407 (P-407) is a tri-block polymer that exhibits concentration-dependent reverse thermal gelation, a characteristic potentially useful for developing sustained release injectable drugs. While some reports suggest that P-407 is 'non-toxic', rodent studies demonstrate that P-407 induces hyperlipidemia, an action that makes this polymer a questionable drug delivery vehicle. Unfortunately, the majority of earlier studies employed supra-physiologic doses of P-407. The present study examined if lower, clinically useful, doses of gel-forming concentrations of P-407 induced hyperlipidemia in rabbits. Male and female rabbits were injected with 5.5 mg/kg (0.025 mL/kg), 27.5 mg/kg (0.125 mL/kg), or 137.5 mg/kg (0.625 mL/kg) of 22% P-407 and the actions of this polymer on blood chemistry were assessed at 6 h, 1 d, 2 d, 7 d, and 14 d following injection. Control rabbits received no injection. The highest dose of P-407 (137.5 mg/kg) significantly increased serum triglycerides and cholesterol in both male and female rabbits with the maximum increase observed at 2 d after injection. Male rabbits were more sensitive to P-407 than females following injection of 137.5 mg/kg P-407. The lower doses of P-407 did not alter serum triglycerides or cholesterol. In all groups, serum triglycerides and cholesterol were at baseline levels by 14 d. P-407 did not affect other blood chemistry parameters. Although P-407 induces a dose-dependent hyperlipidemia in rabbits, low doses of this polymer may be used in controlled release drug delivery applications without the untoward hyperlipidemic effect.
Blonder
J M
JM
RxKinetix, Inc., Louisville, CO 80027, USA. joan@rxkinetix.com
Baird
L
L
Fulfs
J C
JC
Rosenthal
G J
GJ
D000818:Animals; D002784:Cholesterol / Q000097:blood; D003692:Delayed-Action Preparations; D005079:Excipients / Q000633:toxicity*; D005260:Female; D005782:Gels; D006949:Hyperlipidemias / Q000097:blood / Q000139:chemically induced*; D008055:Lipids / Q000097:blood; D008297:Male; D020442:Poloxamer / Q000633:toxicity*; D011817:Rabbits; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D003692:Delayed-Action Preparations; D005079:Excipients; D005782:Gels; D008055:Lipids; D014280:Triglycerides; D020442:Poloxamer; D002784:Cholesterol