Pharmacokinetic-pharmacodynamic correlations in the development of ginger extract as an anticancer agent

Abstract

Anticancer efficacy of ginger phenolics (GPs) has been demonstrated in various in vitro assays and xenograft mouse models. However, only sub-therapeutic plasma concentrations of GPs were detected in human and mouse pharmacokinetic (PK) studies. Intriguingly, a significant portion of GPs occurred as phase II metabolites (mainly glucuronide conjugates) in plasma. To evaluate the disposition of GPs and understand the real players responsible for efficacy, we performed a PK and tissue distribution study in mice. Plasma exposure of GPs was similar on day 1 and 7, suggesting no induction or inhibition of clearance pathways. Both free and conjugated GPs accumulated in all tissues including tumors. While non-cytotoxicity of 6-ginerol glucuronide precluded the role of conjugated GPs in cell death, the free forms were cytotoxic against prostate cancer cells. The efficacy of ginger was best explained by the reconversion of conjugated GPs to free forms by β-glucuronidase, which is over-expressed in the tumor tissue. This previously unrecognized two-step process suggests an instantaneous conversion of ingested free GPs into conjugated forms, followed by their subsequent absorption into systemic circulation and reconversion into free forms. This proposed model uncovers the mechanistic underpinnings of ginger’s anticancer activity despite sub-therapeutic levels of free GPs in the plasma.

Can Ginger (<i>Zingiber officinale</i>) Aqueous Crude Extract Induce Apoptotic Pathways in Drug-Resistance Acute Myeloid Leukemia: <i>In Vitro</i> Study?

“…Recently, Mukkavilli et al [25] explained the Pharmacokinetic-pharmacodynamics correlations in the development of ginger extract as an anticancer agent. Evidence has revealed that 6S, an active constituent of ginger, could induce cell death/apoptosis in many types of cancer cells including, colorectal carcinoma, ovarian cancer, hepatocarcinoma, human lung cancer, breast cancer cells and oral cancer [26] [27] [28] [29].…”

How Safe Is Ginger Rhizome for Decreasing Nausea and Vomiting in Women during Early Pregnancy?

“…Potential toxic effect of ginger have to be studied taking account of the whole plant and its absorption metabolites in humans (glucuronides and sulfates of gingerols, for example), not plant metabolites. Recently, one in vitro study showed that free forms are more cytotoxic compared to the glucuronide conjugates [ 94 ].…”

Gingers and Their Purified Components as Cancer Chemopreventative Agents

“…Mukkavilli et al [35] also found glucuronides of gingerols in plasma. These authors noted [36] that the efficacy of gingerols in tumor cells was best explained by the reconversion of conjugated molecules to the free forms by β-glucuronidase, which is selectively over-expressed in the tumor tissue. This two-step process suggests an instantaneous conversion of ingested free compounds into conjugated forms, followed by their subsequent absorption into systemic circulation and reconversion to the primary molecule in the tumor cells.…”