Pharmacokinetics and toxicity of high-dose human alpha 1-acid glycoprotein infusion in the rat.
The pharmacokinetics of high-dose human alpha 1-acid glycoprotein (AAG) was studied in rats to determine the feasibility of using AAG to alter the tissue distribution of basic drugs. alpha 1-Acid glycoprotein (2.2 g/kg) was administered iv to six male Holtzman rats over a period of 30 min, and serum AAG concentrations were measured by a specific radial immunodiffusion assay. The AAG concentrations were computer fit to a biexponential equation to generate pharmacokinetic constants for an open two-compartment model. The peak serum AAG concentration was 1830 +/- 180 mg/dL at the end of infusion; greater than 20 times the normal value for rats. The central volume of distribution and steady state volume of distribution were 0.09 +/- .02 and 0.15 +/- 0.02 L/kg, respectively. Total body clearance of AAG was 0.065 +/- 0.005 L/kg/h, and the terminal elimination half-life was 19.3 +/- 1.5 h. The AAG administration was tolerated without adverse effect and did not alter systolic blood pressure, the electrocardiogram, creatinine clearance, weight gain, or survival. The results of the histologic examination of various tissues by light microscopy at 30 d post AAG treatment were normal. These data demonstrate that high doses of human AAG can be safely administered to rats and that they produce supraphysiologic serum AAG concentrations.
D000818:Animals; D006439:Hemodynamics / Q000187:drug effects; D007122:Immunoelectrophoresis; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D009961:Orosomucoid / Q000008:administration & dosage* / Q000378:metabolism / Q000633:toxicity; D051381:Rats
D009961:Orosomucoid