Preclinical pharmacokinetic analysis of NOV-002, a glutathione disulfide mimetic

Abstract

SummaryNOV-002 is a glutathione disulfide (GSSG) mimetic that is in Phase III clinical trials for the treatment of advanced non-small cell lung cancer and other 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. Nonlinear pharmacokinetic modeling predicted that the estimated absorption and elimination rate constants correspond to a half-life of ~13 mins with an AUC of 1.18 μg.h/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.

Cocaine-Induced Adaptations in Cellular Redox Balance Contributes to Enduring Behavioral Plasticity

“…The cone voltages were 23 V, 35 V, and 25 V, and the collision energy 13 V, 22 V, and 12 V, respectively. The redox potential (E h ) of thiol/disulfide levels in the nucleus accumbens was calculated from the GSSG and GSH concentrations using the Nernst equation, E h ¼ 7.4: À264 + 30log (GSSG)/(GSH) 2 (Jones et al, 2000;Uys et al, 2010). The values are expressed in mV ± SEM.…”

“…Given that GSH is the most abundant non-protein cellular thiol and redox buffer (Lopez-Mirabal and Winther, 2008), the redox potential can be calculated using GSH and GSSG concentrations through the Nernst equation (Jones et al, 2000;Schafer and Buettner, 2001;Uys et al, 2010). The E h of thiol/disulfide levels in the nucleus accumbens was calculated from the GSSG and GSH concentrations (see Supplementary Table S1 for raw values).…”

Pharmacokinetic analysis and tissue distribution of andrographolide in rat by a validated LC-MS/MS method

“…Besides being used as a single herb, it is also a common constituent of a variety of ayurvedic preparations used in the treatment of chronic malaria, diabetes, hepatic toxicity, common cold and loss of appetite (Cáceres et al, 1999;Chopra et al, 1982;Elango et al, 2011;Kapil et al, 1993;Misra et al, 1992;Rahman et al, 1999;Raina et al, 2013;Roxas & Jurenka, 2007;Zhang & Tan, 2000). Pharmacokinetic studies constitute an important phase in the development of new medicine and also to determine the disposition process (absorption, distribution, metabolism and elimination) for selection of the most appropriate route of administration and dose regimen (Liu et al, 2010;Uys et al, 2010).…”

Kinases and glutathione transferases: selective and sensitive targeting

“…Additionally, the involvement of GST P in cellular signaling was shown with the detection of p38 MAPK, JNK and ERK activation with dose dependent phosphorylation of Akt, JAK2, and STAT5. Clinical studies with NOV-002 were shown the improved tolerance to chemotherapy with increase in survival rate when administered in combination with standard chemotherapeutics in advanced non-small cell lung cancer patients (Townsend et al, 2002;Townsend et al, 2008;Uys et al, 2010). Besides the advancements of cancers in relation to the oxidative stress induced GST activation, recently it was reported that normal keratinocytes may represent a vitiligo-like cytokine pattern after exposure to 4-hydroxy-2-nonenal (HNE), another ROS source.…”