Investigation On Pharmacokinetics, Bio-distribution And Safety Of A Novel Macromolecular Poly Amino Acid-based Mri Contrast Agent

This study aimed to investigate the plasma pharmacokinetics and biodistribution of biocompatible Gd(III) complexes, a new magnetic resonance imaging contrast agent Poly(2-aminoethyl)-aspartic acid-leucine-Gd-DOTA(PL-A2-DOTA-Gd). The pharmacokinetics and biodistribution of PL-A2-DOTA-Gd were investigated in male Wistar rats after intravenous administration at a dose of 0.1 mmol Gd/kg. A simple, sensitive and rapid ICP-OES method was developed and validated for the determination of the Gd content with satisfactory selectivity, linearity and extraction recovery in plasma and various tissues. Main pharmacokinetic parameters were calculated by the PKSolver 2.0 software package and biochemical indicators were used to evaluate the safety of PL-A2-DOTA-Gd. The security was investigated by hemolytic test in vitro and the acute toxicity in rats in vivo.The result showed that the concentration-time curve of PL-A2-DOTA-Gd in the body of rats was fitted for a two-compartment open model of first-order kinetics. The concentration of PL-A2-DOTA-Gd decreased fast in 24 h, and in the hour of 72 h it decreased in degrees, after 72 h it descend slowly. The main pharmacokinetic parameters the half-life of distribution phase was 0.88 ± 0.08 h, and the half-life of elimination phase was 11.83 ± 4.69 h, which were 7.3 and 7.8 fold of the commercially available MRI contrast agent Gd-DOTA, respectively. The volume of distribution was 0.28 ± 0.08 L/kg. Thus, macromolecular PL-A2-DOTA-Gd can significantly enhance blood circulation time, effectively prolong the half life. The distribution of PL-A2-DOTA-Gd was in the order of kidney > liver > heart > lung > spleen. It mainly selectively accumulated in kidney and liver, and it was excreted via renal excretion with some damage to the liver and kidney. At the same time it had good biological compatibility, has no hemolytic compared to small molecule Gd-DOTA. And it had less cytotoxicity than Gd-DOTA. It might do slightly damage to liver and kidney, but have little effect on the body’s overall health situation.