Pharmacokinetics of Plasmid DNA in the Rat

Purpose. The pharmacokinetics of plasmid DNA after IV bolus administration in the rat by following supercoiled (SC), open circular (OC), and linear (L) pDNA forms of the plasmid.Methods. SC, OC, and L pDNA were injected at 2500, 500, 333, and 250 g doses. The concentrations in the bloodstream of OC and L pDNA were monitored.Results. SC pDNA was detectable in the bloodstream only after a 2500 g dose, and had a clearance of 390(±50) ml/min and V_d of 81(±8) ml. The pharmacokinetics of OC pDNA exhibited non-linear characteristics with clearance ranging from 8.3(±0.8) to 1.3(±0.2) ml/min and a V_d of 39(±19) ml. L pDNA was cleared at 7.6(±2.3) ml/min and had a V_d of 37(±17) ml. AUC analysis revealed that 60(±10) % of the SC was converted to the OC form, and nearly complete conversion of the OC pDNA to L pDNA. Clearance of SC pDNA was decreased after liposome complexation to 87(±30) ml/min. However the clearance of OC and L pDNA was increased relative to naked pDNA at an equivalent dose to 37(±9) ml/min and 95(±37) ml/min respectively.Conclusions. SC pDNA is rapidly metabolized and cleared from the circulation. OC pDNA displays non-linear pharmacokinetics. Linear pDNA exhibits first order kinetics. Liposome complexation protects the SC topoform, but the complexes are more rapidly cleared than the naked pDNA.