Suspensions of pro-drug insulin greatly prolong normoglycemic patterns in diabetic rats.
FMS(3)-insulin (2-sulfo-9-fluorenylmethoxycarbonyl)(3)-insulin is a water soluble, inactive-reactivated derivative of insulin with protracted action in vivo. In this study we find that FMS(3)-insulin preserves insulin's capacity to crystallize when associated with Zn(2+) ions or with basic protamine. Zinc or protamine suspended preparations of FMS(3)-insulin manifest substantially prolonged, blood glucose-lowering pharmacokinetic profiles in STZ-treated rats (STZ-rats). A dose of up to 1mg suspended FMS(3)-insulin/STZ rat can be subcutaneously administered with no hypoglycemic episodes at any time point after administration. This dose yielded glucose-lowering profiles with t(1/2) values at the range of 50-70h, turning catabolic STZ-rats into anabolic ones over a period of 2-3 days. The obtained glucose-lowering patterns exceeded 7-8 times in duration those produced by nonhypoglycemic doses of NPH-insulin. In summary, subcutaneous administration of suspended insulin prodrugs, such as FMS(3)-insulin, can bring about prolonged, nonhypoglycemic glucose-lowering profiles, unattainable with insulin preparations, which are known to be active at the time of administration.
Shechter
Yoram
Y
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel. y.shechter@weizmann.ac.il
Tsubery
Haim
H
Fridkin
M
M
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D007328:Insulin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D011479:Protamines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D015032:Zinc / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D011355:Prodrugs; D011479:Protamines; D013311:Streptozocin; D015032:Zinc