title: In vitro biotransformation, in vivo efficacy and pharmacokinetics of antimalarial chalcones.
abstract: 4'-n-Butoxy-2,4-dimethoxy-chalcone (MBC) has been described as protecting mice from an otherwise lethal infection with Plasmodium yoelii when dosed orally at 50 mg/kg/dose, daily for 5 days. In contrast, we found that oral dosing of MBC at 640 mg/kg/dose, daily for 5 days, failed to extend the survivability of P. berghei-infected mice. The timing of compound administration and metabolic activation likely contribute to the outcome of efficacy testing in vivo. Microsomal digest of MBC yielded 4'-n-butoxy-4-hydroxy-2-methoxy-chalcone and 4'-(1-hydroxy-n-butoxy)-2,4-dimethoxy-chalcone. We propose that the latter will hydrolyze in vivo to 4'-hydroxy-2,4-dimethoxy-chalcone, which has greater efficacy than MBC in our P. berghei-infected mouse model and was detected in plasma following oral dosing of mice with MBC. Pharmacokinetic parameters suggest that poor absorption, distribution, metabolism and excretion properties contribute to the limited in vivo efficacy observed for MBC and its analogs.
authors.affiliation: Department of Chemistry, United States Naval Academy, Annapolis, Md 21402, USA. gutterid@usna.edu
authors.forename: Clare E
authors.initials: CE
authors.lastname: Gutteridge
authors.forename: Darshan S
authors.initials: DS
authors.lastname: Thota
authors.forename: Sean M
authors.initials: SM
authors.lastname: Curtis
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kozar
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.forename: Lisa
authors.initials: L
authors.lastname: Xie
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
authors.forename: Constance O
authors.initials: CO
authors.lastname: Asher
authors.forename: Thulan T
authors.initials: TT
authors.lastname: Luong
authors.forename: Lucia
authors.initials: L
authors.lastname: Gerena
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Nichols
authors.forename: Gettayacamin
authors.initials: G
authors.lastname: Montip
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D001711:Biotransformation; D047188:Chalcones / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D010962:Plasmodium berghei / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization; D016019:Survival Analysis; D053719:Tandem Mass Spectrometry
chemical_list: C108857:2,4-dimethoxy-4'-butoxychalcone; C558778:4'-hydroxy-2,4-dimethoxychalcone; D000962:Antimalarials; D047188:Chalcones