title: The potential of Sutherlandia frutescens for herb-drug interaction.
abstract: In Africa, Sutherlandia frutescens is a popular medicinal herb widely consumed by people living with human immunodeficiency virus/AIDS. Concomitant use with antiretroviral drugs has generated concerns of herb-drug interaction (HDI). This study investigated the inhibitory effects of the crude extracts of S. frutescens on the major cytochrome P450 isozymes with the use of pooled human liver microsomes. Its effect on the metabolic clearance of midazolam using cryopreserved hepatocytes was also monitored. The potential of S. frutescens to inhibit human ATP-binding cassette transporters (P-gp and BCRP) and the human organic anion transporting polypeptide (OATP1B1 and OATP1B3) activity was assessed using cell lines overexpressing the transporter proteins. S. frutescens showed inhibitory potency for CYP1A2 (IC(50) = 41.0 µg/ml), CYP2A6 (IC(50) = 160 µg/ml), CYP2B6 (IC(50) = 20.0 µg/ml), CYP2C8 (IC(50) = 22.4 µg/ml), CYP2C9 (IC(50) = 23.0 µg/ml), CYP2C19 (IC(50) = 35.9 µg/ml), and CYP3A4/5 (IC(50) = 17.5 µg/ml [with midazolam1'-hydroxylation]; IC(50) = 28.3 µg/ml [with testosterone 6β-hydroxylation]). Time-dependent (irreversible) inhibition by S. frutescens was observed for CYP3A4/5 (K(I) = 296 µg/ml, k(inact) = 0.063 min(-1)) under the conditions of this study. S. frutescens also delays the production of midazolam metabolites in the hepatocytes, decreasing its clearance by 40%. Furthermore, S. frutescens inhibited P-gp (IC(50) = 324.8 µg/ml), OATP1B1 (IC(50) = 10.4 µg/ml), and OATP1B3 (IC(50) = 6.6 µg/ml). The result indicates the potential for HDI between S. frutescens and the substrates of the affected enzymes, if sufficient in vivo concentration of the extract is attained.
authors.affiliation: Division of Pharmacology, Department of Medicine, University of Stellenbosch, Tygerberg, Cape Town, South Africa. 16669967@sun.ac.za
authors.forename: Pius S
authors.initials: PS
authors.lastname: Fasinu
authors.forename: Heike
authors.initials: H
authors.lastname: Gutmann
authors.forename: Hilmar
authors.initials: H
authors.lastname: Schiller
authors.forename: Alexander-David
authors.initials: AD
authors.lastname: James
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bouic
authors.forename: Bernd
authors.initials: B
authors.lastname: Rosenkranz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D007887:Fabaceae / Q000737:chemistry*; D005260:Female; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D041743:Herb-Drug Interactions; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes; D007700:Kinetics; D018374:LLC-PK1 Cells; D027381:Liver-Specific Organic Anion Transporter 1; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D049990:Membrane Transport Modulators / Q000302:isolation & purification / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008874:Midazolam / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism; D018515:Plant Leaves; D028321:Plant Preparations / Q000302:isolation & purification / Q000494:pharmacology*; D010946:Plants, Medicinal; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013379:Substrate Specificity; D013552:Swine; D013739:Testosterone / Q000378:metabolism; D014162:Transfection
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D027381:Liver-Specific Organic Anion Transporter 1; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D028321:Plant Preparations; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D008874:Midazolam