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Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties.

ABSTRACT: Triterpenoids have been used for medicinal purposes in many Asian countries because of their anti-inflammatory, antioxidant, antiproliferative, anticancer, and anticarcinogenic properties. Bardoxolone methyl, the C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) known as CDDO-Me or RTA 402, is one of the derivatives of synthetic triterpenoids. CDDO-Me has been used for the treatment of chronic kidney disease, cancer (including leukemia and solid tumors), and other diseases. In this review, we will update our knowledge of the clinical pharmacokinetics and pharmacodynamics of CDDO-Me, highlighting its clinical benefits and the underlying mechanisms involved. The role of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)/the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the therapeutic activities of CDDO-Me will be discussed. CDDO-Me contains ?,?-unsaturated carbonyl groups on rings A and C that can generate reversible adducts with the thiol groups of Cys residues in target proteins such as Keap1 and I?B kinase. At low nanomolar concentrations, CDDO-Me protects the cells against oxidative stress via inhibition of reactive oxygen species generation, while CDDO-Me at low micromolar concentrations induces apoptosis by increasing reactive oxygen species and decreasinging intracellular glutathione levels. Through Keap1/Nrf2 and nuclear factor-?B pathways, this agent can modulate the activities of a number of important proteins that regulate inflammation, redox balance, cell proliferation and programmed cell death. In a Phase I trial in cancer patients, CDDO-Me was found to have a slow and saturable oral absorption, a relatively long terminal phase half-life (39 hours at 900 mg/day), nonlinearity (dose-dependent) at high doses (600-1,300 mg/day), and high interpatient variability. As a multifunctional agent, CDDO-Me has improved the renal function in patients with chronic kidney disease associated with type 2 diabetes. CDDO-Me has shown a promising anticancer effect in a Phase I trial. This agent is generally well tolerated, but it may increase adverse cardiovascular events. Presently, it is being further tested for the treatment of patients with chronic kidney disease, cancer, and pulmonary arterial hypertension.

SUBMITTER: Wang YY

PROVIDER: S-EPMC4211867 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties.

Wang Yan-Yang YY Yang Yin-Xue YX Zhe Hong H He Zhi-Xu ZX Zhou Shu-Feng SF

Drug design, development and therapy 20141023

Triterpenoids have been used for medicinal purposes in many Asian countries because of their anti-inflammatory, antioxidant, antiproliferative, anticancer, and anticarcinogenic properties. Bardoxolone methyl, the C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) known as CDDO-Me or RTA 402, is one of the derivatives of synthetic triterpenoids. CDDO-Me has been used for the treatment of chronic kidney disease, cancer (including leukemia and solid tumors), and other diseases ...[more]

PMID: 25364233

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Project description:Oxidative stress plays an important role in the pathogenesis of chronic heart failure (CHF) in many tissues. Increasing evidence suggests that systemic activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling can protect against postinfarct cardiac remodeling by reducing oxidative stress. However, it remains to be elucidated if Nrf2 activation exerts therapeutic effects in the CHF state. Here, we investigated the beneficial hemodynamic effects of bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me), a pharmacological activator of Nrf2, in a rodent model of CHF. Based on echocardiographic analysis, rats at 12 weeks post-myocardial infarction (MI) were randomly split into four groups. CDDO-Me (5 mg/kg, i.p.) was administered daily for another 2 weeks in sham and CHF rats and compared with vehicle treatment. Echocardiographic and hemodynamic analysis suggest that short-term CDDO-Me administration increased stroke volume and cardiac output in CHF rats and decreased left ventricle end-diastolic pressure. Molecular studies revealed that CDDO-Me-induced cardiac functional improvement was attributed to an increase of both Nrf2 transcription and translation, and a decrease of oxidative stress in the noninfarcted areas of the heart. Furthermore, CDDO-Me reduced NF-?B binding and increased Nrf2 binding to the CREB-binding protein, which may contribute to the selective increase of Nrf2 downstream targets, including NADPH Oxidase Quinone 1, Heme Oxygenase 1, Catalase, and Glutamate-Cysteine Ligase Catalytic Subunit, and the attenuation of myocardial inflammation in CHF rats. Our findings suggest that Nrf2 activation may provide beneficial cardiac effects in MI-mediated CHF. SIGNIFICANCE STATEMENT: Chronic heart failure (CHF) is the leading cause of death among the aged worldwide. The imbalance between pro- and antioxidant pathways is a determinant in the pathogenesis of CHF. Systemic activation of Nrf2 and antioxidant protein signaling by bardoxolone methyl may have beneficial effects on cardiac function and result in improvements by enhancing antioxidant enzyme expression and attenuating myocardial inflammation.

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Dataset Information

Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties.

Publications

Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties.

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