Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship

Abstract

Abstract. This study aims to improve the drug oral bioavailability by co-administration with flavonoid inhibitors of the CYP2C isozyme and to establish qualitative and quantitative (QSAR) structure-activity relationships (SAR) between flavonoids and CYP2C. A total of 40 naturally occurring flavonoids were screened in vitro for CYP2C inhibition. Enzyme activity was determined by measuring conversion of tolbutamide to 4-hydroxytolbutamide by rat liver microsomes. The percent inhibition and IC 50 of each flavonoid were calculated and used to develop SAR and QSAR. The most effective flavonoid was orally co-administered in vivo with a cholesterol-reducing drug, fluvastatin, which is normally metabolized by CYP2C. The most potent CYP2C inhibitor identified in vitro was tamarixetin (IC 50 =1.4 μM). This flavonoid enhanced the oral bioavailability of fluvastatin in vivo, producing a >2-fold increase in the area under the concentration-time curve and in the peak plasma concentration. SAR analysis indicated that the presence of a 2,3-double bond in the C ring, hydroxylation at positions 5, 6, and 7, and glycosylation had important effects on flavonoid-CYP2C interactions. These findings should prove useful for predicting the inhibition of CYP2C activity by other untested flavonoid-like compounds. In the present study, tamarixetin significantly inhibited CYP2C activity in vitro and in vivo. Thus, the use of tamarixetin could improve the therapeutic efficacy of drugs with low bioavailability.

Impact of Herbal Medicines like Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida, on Cytochrome P450 2C11 Gene Expression in Rat Liver

“…These findings are supported by several previous studies demonstrated that Nigella sativa's main constituents thymoquinone inhibited CYP2C11 enzyme [2]. In addition, some flavonoids in Trigonella foenum-graecum, such as vitexin, tricin, naringenin, quercetin and tricin-7-O-beta-D-glucopyranoside are known CYP inhibitors [37][38][39]. Moreover, terpenoidal and ferulic acid compounds in Ferula asafoetida are CYP2C modulators [40,41].…”

Artemisinin permeability via Caco-2 cells increases after simulated digestion of Artemisia annua leaves

“…For example, De Magalhães et al showed that tea infusions made from various A. annua cultivars inhibited CYP3A4 (Melillo de Magalhães et al, 2012), an enzyme present in the intestine involved in the metabolism of artemisinin (Svensson and Ashton, 1999). Quercetin, a flavonoid found in A. annua , also increased the absorption of doxorubicin in rats (Choi et al, 2011), while tamarixetin, another flavonoid, increased absorption of fluvastatin in rats (Wang et al, 2014). Further, other studies showed that flavonoids found in A. annua , such as quercetin and rutin, inhibited CYP3A4 as well as other cytochrome P450 enzymes that mediate the metabolism of artemisinin (Wang et al, 2014).…”

“…Quercetin, a flavonoid found in A. annua , also increased the absorption of doxorubicin in rats (Choi et al, 2011), while tamarixetin, another flavonoid, increased absorption of fluvastatin in rats (Wang et al, 2014). Further, other studies showed that flavonoids found in A. annua , such as quercetin and rutin, inhibited CYP3A4 as well as other cytochrome P450 enzymes that mediate the metabolism of artemisinin (Wang et al, 2014).…”

Review of scientific evidence of medicinal convoy plants in traditional Persian medicine

“…Accordingly, oral coadministrations of flavonoids can improve the therapeutic effects of drugs with low bioavailability. [ 59 61 62 ]…”