title: Inhibition of CYP2B6 by Medicinal Plant Extracts: Implication for Use of Efavirenz and Nevirapine-Based Highly Active Anti-Retroviral Therapy (HAART) in Resource-Limited Settings.
abstract: Highly active antiretroviral therapy (HAART) has greatly improved health parameters of HIV infected individuals. However, there are several challenges associated with the chronic nature of HAART administration. For populations in health transition, dual use of medicinal plant extracts and conventional medicine poses a significant challenge. There is need to evaluate interactions between commonly used medicinal plant extracts and antiretroviral drugs used against HIV/AIDS. Efavirenz (EFV) and nevirapine (NVP) are the major components of HAART both metabolized by CYP2B6, an enzyme that can potentially be inhibited or induced by compounds found in medicinal plant extracts. The purpose of this study was to evaluate the effects of extracts of selected commonly used medicinal plants on CYP2B6 enzyme activity. Recombinant human CYP2B6 was used to evaluate inhibition, allowing the assessment of herb-drug interactions (HDI) of medicinal plants Hyptis suaveolens, Myrothamnus flabellifolius, Launaea taraxacifolia, Boerhavia diffusa and Newbouldia laevis. The potential of these medicinal extracts to cause HDI was ranked accordingly for reversible inhibition and also classified as potential time-dependent inhibitor (TDI) candidates. The most potent inhibitor for CYP2B6 was Hyptis suaveolens extract (IC50 = 19.09 ± 1.16 µg/mL), followed by Myrothamnus flabellifolius extract (IC50 = 23.66 ± 4.86 µg/mL), Launaea taraxacifolia extract (IC50 = 33.87 ± 1.54 µg/mL), and Boerhavia diffusa extract (IC50 = 34.93 ± 1.06 µg/mL). Newbouldia laevis extract, however, exhibited weak inhibitory effects (IC50 = 100 ± 8.71 µg/mL) on CYP2B6. Launaea taraxacifolia exhibited a TDI (3.17) effect on CYP2B6 and showed a high concentration of known CYP450 inhibitory phenolic compounds, chlorogenic acid and caffeic acid. The implication for these observations is that drugs that are metabolized by CYP2B6 when co-administered with these herbal medicines and when adequate amounts of the extracts reach the liver, there is a high likelihood of standard doses affecting drug plasma concentrations which could lead to toxicity.
authors.affiliation: Division of Human Genetics, Department of Pathology &amp; Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa. THMNIC023@myuct.ac.za.|School of Medical Sciences, University of Cape Coast, Cape Coast, PMB, Ghana. THMNIC023@myuct.ac.za.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Thomford
authors.affiliation: Division of Clinical Pharmacology, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town 7602, South Africa. charzos@yahoo.com.
authors.forename: Charles
authors.initials: C
authors.lastname: Awortwe
authors.affiliation: International Center for Genetic Engineering and Biotechnology (ICGEB), Cape Town component, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa. kd.dzobo@uct.ac.za.|Division of Medical Biochemistry, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa. kd.dzobo@uct.ac.za.
authors.forename: Kevin
authors.initials: K
authors.lastname: Dzobo
authors.affiliation: School of Medical Sciences, University of Cape Coast, Cape Coast, PMB, Ghana. a.faustina@uccsms.edu.gh.
authors.forename: Faustina
authors.initials: F
authors.lastname: Adu
authors.affiliation: Division of Medical Virology, Department of Pathology &amp; Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa. denis.chopera@uct.ac.za.
authors.forename: Denis
authors.initials: D
authors.lastname: Chopera
authors.affiliation: Division of Human Genetics, Department of Pathology &amp; Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa. ambroise.wonkam@uct.ac.za.
authors.forename: Ambroise
authors.initials: A
authors.lastname: Wonkam
authors.affiliation: Division of Human Genetics, Department of Pathology &amp; Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa. michelle.skelton@uct.ac.za.
authors.forename: Michelle
authors.initials: M
authors.lastname: Skelton
authors.affiliation: Division of Chemical Pathology, Department of Pathology &amp; Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa. dee.blackhurst@uct.ac.za.
authors.forename: Dee
authors.initials: D
authors.lastname: Blackhurst
authors.affiliation: Division of Human Genetics, Department of Pathology &amp; Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa. collet.dandara@uct.ac.za.
authors.forename: Collet
authors.initials: C
authors.lastname: Dandara
mesh_terms: D000480:Alkynes; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines / Q000494:pharmacology; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics / Q000378:metabolism; D065686:Cytochrome P-450 CYP2B6 Inhibitors / Q000737:chemistry / Q000494:pharmacology; D041743:Herb-Drug Interactions; D006801:Humans; D019684:Magnoliopsida / Q000737:chemistry; D019829:Nevirapine / Q000494:pharmacology; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology*; D010946:Plants, Medicinal / Q000737:chemistry*
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D065686:Cytochrome P-450 CYP2B6 Inhibitors; D010936:Plant Extracts; D019829:Nevirapine; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz
keywords: CYP450; herb-drug interactions; recombinant human CYPs; reversible inhibition; time-dependent inhibition