Critical pharmacokinetic and pharmacodynamic drug-herb interactions in rats between warfarin and pomegranate peel or guava leaves extracts

Abstract

BackgroundIn-depth information of potential drug-herb interactions between warfarin and herbal compounds with suspected anticoagulant blood thinning effects is needed to raise caution of concomitant administration. The current study aimed to investigate the impact of co-administration of pomegranate peel and guava leaves extracts, including their quality markers namely; ellagic acid and quercetin, respectively, on warfarin’s in vivo dynamic activity and pharmacokinetic actions, in addition to potential in vitro cytochrome P450 enzymes (CYP) inhibition.MethodsInfluence of mentioned extracts and their key constituents on warfarin pharmacodynamic and kinetic actions and CYP activity were evaluated. The pharmacodynamic interactions were studied in Sprague Dawley rats through prothrombin time (PT) and International Normalized Ratio (INR) measurements, while pharmacokinetic interactions were detected in vivo using a validated HPLC method. Furthermore, potential involvement in CYP inhibition was also investigated in vitro on isolated primary rat hepatocytes.ResultsPreparations of pomegranate peel guava leaf extract, ellagic acid and quercetin in combination with warfarin were found to exert further significant increase on PT and INR values (p < 0.01) than when used alone (p < 0.05). Pomegranate peel extract showed insignificant effects on warfarin pharmacokinetics (p > 0.05), however, its constituent, namely, ellagic acid significantly increased warfarin Cmax (p < 0.05). Guava leaves extract and quercetin resulted in significant increase in warfarin Cmax when compared to control (p < 0.01). Furthermore, guava leaves extract showed a significant effect on changing the AUC, CL and Vz. Significant reduction in CYP2C8, 2C9, and 3A4 was seen upon concomitant use of warfarin with ellagic acid, guava leaves and quercetin, unlike pomegranate that insignificantly affected CYP activities.ConclusionAll combinations enhanced the anticoagulant activity of warfarin as the results of in vivo and in vitro studies were consistent. The current investigation confirmed serious drug herb interactions between warfarin and pomegranate peel or guava leaf extracts. Such results might conclude a high risk of bleeding from the co-administration of the investigated herbal drugs with warfarin therapy. In addition, the results raise attention to the blood-thinning effects of pomegranate peel and guava leaves when used alone.

Current trends in drug metabolism and pharmacokinetics

“…For example, data show that ellagic acid from pomegranate peel guava leaf extract can significantly increase the AUC of warfarin with concomitant use. A significant reduction in CYP2C8, 2C9, and 3A4 activity was the main reason for this interaction 23 .…”

“…UGT1A4 is involved in the glucuronidation of metizolam 42 . Other UGT isoforms involved endogenous and exogenous substrates are listed in Table 2 23 , 43, 44, 45, 46.…”

Effects of naringenin on the pharmacokinetics of tofacitinib in rats

“…However, people are becoming increasingly aware of the importance of DDIs. In the last few years, several studies on the interactions between flavonoids and drugs have been reported (Seden et al 2010;Alnaqeeb et al 2019;Zhao et al 2019). Given the potential antiinflammatory effects of naringenin, it is often used together with tofacitinib for the treatment of rheumatoid arthritis in Chinese clinics Ananth et al 2016;Banerjee et al 2017).…”

Strong and Selective Inhibitory Effects of the Biflavonoid Selamariscina A against CYP2C8 and CYP2C9 Enzyme Activities in Human Liver Microsomes

“…Surya Sandeep et al (2014) reported that naringenin significantly increases the bioavailability of orally administered felodipine, a P-glycoprotein and CYP3A4 substrate drug, in rats, through the inhibition of intestinal P-gp and CYP3A4 [13]. Alnaqeeb et al (2019) reported that quercetin and guava leaf extracts in combination with warfarin exert a greater increase on warfarin's C max and International Normalized Ratio values than when used alone, indicating the inhibition of CYP2C8, 2C9 and 3A4, major warfarin-metabolizing enzymes [14]. Biflavonoids, formed by the covalent bond between two monoflavonoids, are a subclass of flavonoid [15].…”