Pharmacokinetics of antiviral polyoxometalates in rats.
Polyoxometalates are soluble mineral compounds formed principally of oxide anions and early transition metal cations. The polyoxometalates K12H2[P2W12O48].24H2O (JM 1591), K10[P2W18Zn4(H2O)2O68].20H2O (JM 1596), and [(CH3)3NH]8[Si2W18Nb6O77] (JM 2820) demonstrate potent antiviral activity against human immunodeficiency virus types 1 and 2, herpes simplex virus, and cytomegalovirus in vitro. The preclinical pharmacokinetics of these three compounds were characterized after single-dose intravenous administration of 50 mg/kg to rats. Plasma, urine, and feces were collected for 168 h, and polyoxometalate concentrations were determined by atomic emission. Serum protein binding was measured by equilibrium dialysis. All three compounds were highly bound to serum proteins in a concentration-dependent manner. Total and unbound concentrations of the three compounds in plasma declined in a triexponential 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 total 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 JM 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 glomerular filtration rate (0.086 liter/h/kg), suggesting this polyoxometalate underwent renal tubular reabsorption. However, JM 1591 and JM 2820 appeared to undergo tubular secretion. The fraction of the dose recovered 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 polyoxometalate was recovered in feces. The steady-state volume of distribution based on total concentrations averaged 1.44 liters/kg for JM 1591, 2.39 liters/kg for JM 1596, and 0.59 liter/kg for JM 2820, indicating moderate to wide distribution throughout the body. All three compounds were detected in various tissues 1 week after single-dose administrations, with 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.
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Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602.
Boudinot
F D
FD
Boudinot
S G
SG
Henson
G W
GW
Bossard
G E
GE
Martellucci
S A
SA
Ash
P W
PW
Fricker
S P
SP
Darkes
M C
MC
Theobald
B R
BR
D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D009942:Organometallic Compounds / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013054:Spectrophotometry, Atomic; D017973:Tungsten Compounds / Q000097:blood / Q000493:pharmacokinetics*
D000998:Antiviral Agents; D001798:Blood Proteins; D009942:Organometallic Compounds; D017973:Tungsten Compounds; C087530:JM 1596; C087529:JM 2820; C087531:JM 1591