PHARMACOKINETICS OF ANTIVIRAL POLYOXOMETALATES IN RATS

Polyoxometalates are soluble mineral compounds formed principally of o xide anions and early transition metal cations. The polyoxometalates K 12H2[P2W12O48].24H(2)O (JM 1591), K-10[P2W18Zn4(H2O)(2)O-68].2OH(2)O ( JM 1596), and [(CH3)(3)NH](8)[Si2W18Nb6O77] (JM 2820) demonstrate pote nt antiviral activity against human immunodeficiency virus types 1 and 2, herpes simplex: virus, and cytomegalovirus in vitro. The preclinic al pharmacokinetics of these three compounds were characterized after single-dose intravenous administration of 50 mg/kg to rats. Plasma, ur ine, and feces were collected for 168 h, and polyoxometalate concentra tions were determined by atomic emission. Serum protein binding was me asured by equilibrium dialysis. All three compounds were highly bound to serum proteins in a concentration-dependent manner. Total and unbou nd concentrations of the three compounds in plasma declined in a triex ponential manner with terminal half-lives of 246.0 +/- 127.0, 438.4 +/ - 129.4, and 32.2 +/- 5.37 h (mean +/- standard deviation) for JM 1591 , JM 1596, and JM 2820, respectively. Systemic clearances based on tot al concentrations in plasma were low, averaging 0.016 +/- 0.002, 0.015 +/- 0.002, and 0.018 +/- 0.003 liter/h/kg for JM 1591, JM 1596, and J M 2820, respectively. The clearances of unbound compounds from plasma averaged 0.966 +/- 0.136, 0.050 +/- 0.005, and 0.901 +/- 0.165 liter/h /kg for JM 1591, JM 1596, and JM 2820, respectively. For JM 1596, the clearance of unbound compound from the kidneys was lower than the glom erular filtration rate (0.086 liter/h/kg), suggesting this polyoxometa late underwent renal tubular reabsorption. However, JM 1591 and JM 282 0 appeared to undergo tubular secretion. The fraction of the dose reco vered in urine was 11.5, 46.8, and 10.6% for JM 1591, JM 1596, and JM 2820, respectively. Approximately 5% of the dose of each polyoxometala te was recovered in feces. The steady-state volume of distribution bas ed on total concentrations averaged 1.44 liters/kg for JM 1591, 2.39 l iters/kg for JM 1596, and 0.59 liter/kg for JM 2820, indicating modera te to wide distribution throughout the body. All three compounds were detected in various tissues 1 week after single-dose administration,,v ith the highest levels found in the kidneys and liver. The results of this study indicate that the disposition of polyoxometalates is highly dependent on their molecular structure.