Non-linear renal and biliary clearances of antiviral polyoxometalates in rats

The polyoxometalates, JM 1591 (K12H2[P2W12O48].24 H2O), JM 1596 (K10[P2W18Zn4(H2O)2O68].20 H2O), and JM 2820 ([Me3NH]8[Si2W18Nb6O77]) have been shown to have potent activity against HIV-1 and HIV-2. The pharmacokinetics of JM 1591, JM 1596 and JM 2820 after intravenous administration of 50 mg/kg were investigated in rats. Renal and biliary clearances of the three compounds were found to be dependent on unbound plasma polyoxometalate concentration. Computer modeling was performed by fitting nonlinear pharmacokinetic models simultaneously to unbound plasma concentration, urinary excretion rate and biliary excretion rate versus time data. The renal clearances of JM 1591 and JM 2820 were described by glomerular filtration, saturated active tubular secretion at all plasma concentrations observed and saturable active tubular reabsorption. The urinary excretion of JM 1596 was characterized by glomerular filtration, saturable active tubular secretion and apparent linear reabsorption. Biliary clearances of all three polyoxometalates were described by a Michaelis-Menten function.