Pharmacokinetic properties and metabolism of a new potent antimalarial N-alkylamidine compound, M64, and its corresponding bioprecursors.
Antimalarial activities and pharmacokinetics of the bis-alkylamidine, M64, and its amidoxime, M64-AH, and O-methylsulfonate, M64-S-Me, derivatives were investigated. M64 and M64-S-Me had the most potent activity against the Plasmodium falciparum growth (IC(50)<12nM). The three compounds can clear the Plasmodium vinckei infection in mice (ED(50)<10mg/kg). A liquid chromatography-mass spectrometry method was validated to simultaneously quantify M64 and M64-AH in human and rat plasma. M64 is partially metabolized to M64-monoamidoxime and M64-monoacetamide by rat and mouse liver microsomes. The amidoxime M64-AH undergoes extensive metabolism forming M64, M64-monoacetamide, M64-diacetamide and M64-monoamidoxime. Strong interspecies differences were observed. The pharmacokinetic profiles of M64, M64-AH and M64-S-Me were studied in rat after intravenous and oral administrations. M64 is partially metabolized to M64-AH; while M64-S-Me is rapidly and totally converted to M64 and M64-AH. M64-AH is mostly oxidized to the inactive M64-diacetamine while its N-reduction to the efficient M64 is a minor metabolic pathway. Oral dose of M64-AH was well absorbed (38%) and converted to M64 and M64-diacetamide. This study generated substantial information about the properties of this class of antimalarial drugs. Other routes of synthesis will be explored to prevent oxidative transformation of the amidoxime and to favour the N-reduction.
Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy, 15 Avenue Ch. Flahault, Montpellier I University, Montpellier Cedex 5, France.
Delphine
D
Margout
Florence
F
Gattacceca
Georges
G
Moarbess
Sharon
S
Wein
Christophe
C
Tran van Ba
Samuel
S
Le Pape
Olivier
O
Berger
Roger
R
Escale
Henri J
HJ
Vial
Françoise M M
FM
Bressolle
D000473:Alkanes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000578:Amidines / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001711:Biotransformation; D002138:Calibration; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008288:Malaria / Q000188:drug therapy / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D010091:Oximes / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D012015:Reference Standards; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization; D013451:Sulfonic Acids / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*
C518513:1,12-bis(N,N'-acetamidinyl)dodecane; C557206:1,12-bis(N,N'-hydroxyacetamidinyl)dodecane; C557207:1,12-bis(N,N'-methylsulfonyloxyacetamidinyl)dodecane; D000473:Alkanes; D000578:Amidines; D000962:Antimalarials; D010091:Oximes; D011355:Prodrugs; D013451:Sulfonic Acids