Abstract:
Clinically important herb-drug interactions have been reported for several herbs including herbal beverages. However, studies investigating interaction potentials of widely consumed aqueous beverage of Hibiscus sabdariffa (ABHS), which possesses antihypertensive and antihyperlipidemic properties, are scarce. Therefore, this study was designed to evaluate in vitro and in vivo interactions of ABHS with probe substrates of cytochrome P450 (CYP) isoforms responsible for over 70% metabolism of drugs.
Questionnaire-guided survey was conducted among randomly selected staff (398) and students (910) of University of Ibadan on the use of ABHS. Subsequently, in vitro inhibition of eight selected CYP isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), by ethanolic and aqueous extracts of Hibiscus sabdariffa calyces (AEHS) were estimated in human liver microsomal incubations, by monitoring specific metabolite(s) of appropriate CYP probe substrates. This was followed by open, randomised, two-period cross-over design to evaluate in vivo inhibitory effect of ABHS on CYP1A2 and CYP2D6 using phenotypic metabolic ratios (PMR) of caffeine and metoprolol, respectively in 27 healthy human volunteers. Pharmacodynamic interactions between AEHS and simvastatin were evaluated using 23 factorial experimental design (FED) in hyperlipidemia-induced Wistar rats at low doses of AEHS (250 mg/kg); simvastatin (10 mg/kg) and high doses of AEHS (500 mg/kg); simvastatin (20 mg/kg). Effect of ABHS on the pharmacokinetic parameters of caffeine and simvastatin (CYP3A4 substrate) was evaluated using cross-over design in six healthy human volunteers to determine specific interaction profile. Blood samples were collected at 4-hour for PMR and at specific times over a 24-hour period for pharmacokinetic study. Probe drugs and metabolites were analysed in their respective matrices with liquid chromatography tandem mass spectrophotometer. Descriptive statistics, non-linear regression and one compartment pharmacokinetic model were used to analyse the data at α0.05.
Most (96.9%) respondents had used ABHS, while 12.5% co-administered it with their medications. Ethanolic and AEHS weakly inhibited the eight selected CYP isoforms in vitro, with 50% inhibitory concentration > 100 μg/mL. However, ABHS lacked corresponding significant in vivo inhibitory effect on CYP1A2 and CYP2D6 using PMR. Pharmacodynamic interactions between low-dose AEHS and low-dose simvastatin resulted in 38.3%, 57.4% and 80.6% reduction in total cholesterol, triglyceride and low density lipoprotein cholesterol levels, respectively; similar to high-dose simvastatin but significantly higher than low-dose simvastatin alone. Also, ABHS decreased absorption rate constant (Ka) of caffeine by 30.0%, and increased its elimination rate constant (Ke), time to reach maximum plasma concentration (Tmax), and peak plasma concentration (Cmax) by 21.0%, 23.0%, and 10.0%, respectively. Further, ABHS reduced the apparent clearance and Ke of simvastatin by 52.0% and 18.0%, respectively, while Tmax increased by 25.0% and Cmax decreased by 18.0%.
Aqueous extract of Hibiscus sabdariffa enhanced antihyperlipidemic activity of simvastatin when co-administered at low doses. Although, aqueous beverage of Hibiscus sabdariffa did not inhibit cytochrome P450 1A2 and 2D6, it reduced simvastatin clearance and affected other pharmacokinetic parameters of caffeine and simvastatin. Caution should therefore be taken with this beverage while on medications.
Keywords: Hibiscus sabdariffa, Herb-drug interaction, Cytochrome P450 isoforms, Simvastatin, Caffeine.
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