title: In vitro antimalarial interactions between mefloquine and cytochrome P450 inhibitors.
abstract: The treatment and control of malaria is becoming increasingly difficult due to resistance of Plasmodium falciparum strains resistance to commonly used antimalarials. Combination therapy is currently the strategy for combating multi-drug resistant falciparum malaria, through exploiting phamacodynamic synergistic effect and delaying the emergence of drug resistance. The objective of the present study was to investigate antimalarial activity of inhibitors of cytochrome P450 (CYP) enzyme including their interactions with the antimalarial mefloquine against chloroquine-resistant (K1) and chloroquine-sensitive (3D7) P. falciparum clones in vitro. Results showed IC(50) (drug concentration which produces 50% schizont maturation inhibition) values [mean (range)] of mefloquine against K1 and 3D7 clones to be 8.6 (8.0-9.3) and 12.1 (10.5-13.8) nM, respectively. The corresponding values for the IC(50) of quinidine were 32.2 (31.9-32.5) and 28.7 (28.4-29.0) nM, and for ketoconazole were 3.9 (3.7-4.1) and 4.8 (4.6-5.1) microM, respectively. Analysis of isobologram revealed a trend of decreasing of fraction IC(50) (FIC), which indicates synergistics of the either quinidine or ketoconazole with mefloquine for both chloroquine-resistant and chloroquine-sensitive clones.
authors.affiliation: Thammasat University, Thailand.
authors.forename: Raewadee
authors.initials: R
authors.lastname: Wisedpanichkij
authors.forename: Wanna
authors.initials: W
authors.lastname: Chaijaroenkul
authors.forename: Piyanan
authors.initials: P
authors.lastname: Sangsuwan
authors.forename: Jintana
authors.initials: J
authors.lastname: Tantisawat
authors.forename: Kanyarat
authors.initials: K
authors.lastname: Boonprasert
authors.forename: Kesara
authors.initials: K
authors.lastname: Na-Bangchang
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000494:pharmacology*; D015767:Mefloquine / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011802:Quinidine / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011802:Quinidine; D007654:Ketoconazole; D015767:Mefloquine