FMS3-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 FMS3-insulin preserves insulin's capacity to crystallize when associated with Zn2+ ions or with basic protamine. Zinc or protamine suspended preparations of FMS3-insulin manifest substantially prolonged, blood glucose-lowering pharmacokinetic profiles in STZ-treated rats (STZ-rats). A dose of up to 1 mg suspended FMS3-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 50-70 h, 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 FMS3-insulin, can bring about prolonged, nonhypoglycemic glucose-lowering profiles, unattainable with insulin preparations, which are known to be active at the time of administration. (C) 2003 Elsevier Inc. All rights reserved.