Abstract
Seven medicinal plants popularly used for treating malaria in West Africa were selected to assess herb-drug interaction potential through a series of in vitro methods. Fluorescent cytochrome P450 (CYP) assays were conducted using the recombinant CYP enzymes for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 to assess the effect of the methanolic extracts on the metabolic activity of CYPs. Secondly, the inhibitory effect of the extracts was evaluated on P-glycoproteins (P-gp) using calcein-AM, a fluorescent substrate, in MDCK-II and hMDR1-MDCK-II cells. The inhibition of P-gp activity was determined as a reflection of increase in calcein-AM uptake. Additionally, the enzyme induction potential of the extracts was assessed through the modulation of PXR activity in HepG2 cells transiently transfected with pSG5-PXR and PCR5 plasmid DNA. Significant inhibition of CYP activity (IC50 < 10 µg/mL) was observed with the following herbs: A. muricata [CYP2C9, 3A4 and CYP2D6]; M. indica [CYP2C9]; M. charantia [CYP2C9 and CYP2C19]; P. amarus [CYP2C19, CYP2C9 and CYP3A4]; T. diversifolia [CYP2C19 and CYP3A4]. Extracts of four herbs (P. amarus, M. charantia, T. diversifolia and A. muricata) exhibited significant inhibition of P-gp with IC50 values (µg/mL) of 17 ± 1, 16 ± 0.4, 26 ± 1, and 24 ± 1, respectively. In addition, four herbs (A. mexicana, M. charantia, P. amarus and T. diversifolia) showed a >two-fold increase in induction in PXR activity. These findings suggest that these herbs may be capable of eliciting herb-drug interactions if consumed in high quantities with concomitant use of conventional therapies.
Highlights
Malaria remains one of the leading causes of death in several countries of the world
Herb-drug interaction (HDI) are often pharmacokinetic in nature, in which case, the presence of the herbal products alters the metabolism and/or transport of the co-administered drug
P-gp inhibition with EC50 values of 17 ± 1.4, 16 ± 0.3, 26 ± 1.1, 24 ± 0.9, respectively. These findings suggest that the herbal products, if taken in sufficient quantities, may inhibit the. These findings suggest that the herbal products, if taken in sufficient quantities, may inhibit the activity activity of intestinal P-gp and alter the absorption kinetics of its substrates
Summary
Malaria remains one of the leading causes of death in several countries of the world. Artemisinin-based combination therapy (ACT) has been a mainstay of treatment, as recommended by the WHO. In resource-poor countries, there is still heavy reliance on traditional herbal remedies for the treatment of malaria [2]. Herb-drug interaction (HDI) is the most important clinical risk in concomitant herb-drug administrations. HDIs are often pharmacokinetic in nature, in which case, the presence of the herbal products alters the metabolism and/or transport of the co-administered drug. Pharmacokinetic HDIs pose more risk to the drugs that have narrow therapeutic windows [4]. Two extremes of clinical experience are possible—therapy failure due to enzyme induction that leads to faster drugs clearance, and toxicity as a result of enzyme inhibition and drug accumulation
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