Abstract
Context Both nobiletin (NBL) and glycyrrhizin (GL) have anti-inflammatory and antitumor properties. These agents may be co-administered in the clinic. However, the drug–drug interaction between them is not clear. Objective The drug–drug interaction between GL and NBL was investigated, to clarify the effect of GL on the pharmacokinetics of NBL, and its main mechanism. Materials and methods The pharmacokinetic profiles of oral administration of NBL (50 mg/kg) in Sprague-Dawley rats of two groups with six each, with or without pre-treatment of GL (100 mg/kg/day for 7 days), were investigated. The effects of GL on the metabolic stability and transport of NBL were also investigated through the rat liver microsome and Caco-2 cell transwell models. Results The results showed that GL significantly decreased the peak plasma concentration (from 1.74 ± 0.15 to 1.12 ± 0.10 μg/mL) and the t1/2 (7.44 ± 0.65 vs. 5.92 ± 0.68) of NBL, and the intrinsic clearance rate of NBL was increased by the pre-treatment with GL (39.49 ± 2.5 vs. 48.29 ± 3.4 μL/min/mg protein). The Caco-2 cell transwell experiments indicated that GL could increase the efflux ratio of NBL from 1.61 to 2.41. Discussion and conclusion These results indicated that GL could change the pharmacokinetic profile of NBL, via increasing the metabolism and efflux of NBL in rats. It also suggested that the dose of NBL should be adjusted when co-administrated with GL in the clinic.
Highlights
Nobiletin (NBL) is a naturally occurring polymethoxy-flavonoid, commonly found in citrus fruit peels (Nogata et al 2006)
As NBL is a substrate of CYP3A4, and its transportation mediated by P-gp, the drug–drug interaction might affect the pharmacokinetics of NBL, and influence the bioavailability
The mean plasma concentration–time curves of NBL with or without GL are shown in Figure 1, and the pharmacokinetic parameters were calculated using the noncompartmental method with the DAS 3.0 pharmacokinetic software (Chinese Pharmacological Association, Anhui, China)
Summary
Nobiletin (NBL) is a naturally occurring polymethoxy-flavonoid, commonly found in citrus fruit peels (Nogata et al 2006). It has been reported that NBL can induce apoptosis of human breast cancer cells (Liu et al 2018), inhibit the viability of human renal carcinoma cells (Wei et al 2019) and exert or not exert antileukemic effects (Chen et al 2018). Combination of different drugs can affect the bioavailability of drugs and the anticancer effect. Combination of nobiletin and sorafenib exerted synergistic effects on the inhibition of metastatic prostate cancer cell viability (Guney Eskiler et al 2019). As NBL is a substrate of CYP3A4, and its transportation mediated by P-gp, the drug–drug interaction might affect the pharmacokinetics of NBL, and influence the bioavailability
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