Preclinical pharmacokinetic analysis of NOV-002, a glutathione disulfide mimetic.
NOV-002 is a glutathione disulfide (GSSG) mimetic that is the subject of clinical investigation in oncology indications. GSSG is reduced by glutathione reductase (GR) to form glutathione (GSH), thereby maintaining redox homeostasis. The purpose of the study was to report the pharmacokinetic properties of NOV-002 and evaluate the effect that NOV-002 elicits in redox homeostasis. The pharmacokinetic analysis and tissue distribution of NOV-002 and GSH was evaluated in mice following a dose of 250 mg/kg, i.p. The redox potential and total protein thiol status was calculated. Here we show that NOV-002 is a substrate for GR and that GSH is a primary metabolite. Non-linear pharmacokinetic modeling predicted that the estimated absorption and elimination rate constants correspond to a half-life of approximately 13 min with an AUC of 1.18 μgh/mL, a C(max) of 2.16 μg/ml and a volume of distribution of 42.61 L/kg. In addition, measurement of the redox potential and total protein thiol status indicated the generation of a transient oxidative signal in the plasma compartment after administration of NOV-002. These results indicate that NOV-002 exerts kinetic and dynamic effects in mice consistent with the GSSG component as the active pharmacological constituent of the drug. A longer-lasting decrease in total plasma free thiol content was also seen, suggesting that the oxidative effect of the GSSG from NOV-002 was impacting redox homeostasis.
Uys
J D
JD
Cell and Molecular Pharmacology, Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, P.O. Box 250505, Charleston, SC 29425, USA.
Manevich
Y
Y
Devane
L C
LC
He
L
L
Garret
T E
TE
Pazoles
C J
CJ
Tew
K D
KD
Townsend
D M
DM
D000818:Animals; D002945:Cisplatin / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D019803:Glutathione Disulfide / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D005980:Glutathione Reductase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017711:Nonlinear Dynamics; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000097:blood; D014018:Tissue Distribution
D004338:Drug Combinations; C529375:NOV 002; D013438:Sulfhydryl Compounds; D005980:Glutathione Reductase; D005978:Glutathione; D002945:Cisplatin; D019803:Glutathione Disulfide