Десбутиллюмфантрин

Description

Desbutillumfantrine is an active metabolite of the antimalarial drug lumefantrine. It is formed in the liver under the action of the enzymes CYP3A4 and CYP3A5, which cleave the butyl group from the side chain of the molecule. The metabolite has higher antimalarial activity in vitro than lumefantrine itself: the IC50 of desbutyllumphantrine is 4-5 times lower, that is, the effective concentration is lower. The substance is active against both chloroquine-sensitive and resistant strains of Plasmodium falciparum, the causative agent of tropical malaria, with IC50 values ​​of 9 and 9.5 nM, respectively.

Basic Attributes

• CAS No: 355841-11-1
• Chemical formula: C26H24Cl3NO
• Molecular Weight: 472.83
• Exact weight: 472.83
• DSSTox ID: DTXSID10433027
• PSA specifications: 32.3
• XLogP3: 7

The high value of XLogP3 (7) indicates the pronounced lipophilicity of the molecule - a typical property for antimalarial drugs of the arylmethanol group, which ensures the accumulation of the substance in the membranes of erythrocytes affected by Plasmodium and explains the long period of elimination from the body.

Clinical significance

Lumefantrine is used in combination with artemether (artemisinin-based combination therapy, ACT) to treat uncomplicated Plasmodium falciparum malaria. The systemic exposure of lumefantrine itself is 85–300 times higher than the exposure of desbutyllumfantrine, however, it is the concentration of the metabolite on the 7th day of therapy that correlates better with treatment outcome than the concentration of the parent drug - this makes desbutyllumfantrine an important pharmacokinetic marker of the effectiveness of therapy.

• therapeutic monitoring marker during treatment with artemether-lumefantrine
• reference standard for bioanalytical methods (HPLC-MS/MS) for pharmacokinetic studies
• interaction studies with antiretroviral drugs in co-infected patients
• studying the effectiveness of therapy in pregnant women with uncomplicated malaria

Mechanism of antimalarial action

Like the related arylmethanol antimalarials, desbutyllumfantrine interferes with heme detoxification in the Plasmodium digestive vacuole, preventing the polymerization of toxic free heme into harmless hemozoin. The accumulation of free heme damages the membranes of the parasite and leads to its death.

Storage and transportation conditions

Store in a sealed container protected from light at a reduced temperature (in accordance with the recommendations of the reference standard supplier), avoid freeze-thaw cycles when working with solutions for analytical purposes.

Synonyms

9H-Fluorene-4-methanol, α-[(butylamino)methyl]-2,7-dichloro-9-[(4-chlorophenyl)methylene]-, (9Z)-; (9Z)-α-[(Butylamino)methyl]-2,7-dichloro-9-[(4-chlorophenyl)methylene]-9H-fluorene-4-methanol; Desbutyl-benflumetol.

Place in the therapeutic scheme

Artemether-lumefantrine remains one of the main treatment regimens for uncomplicated malaria recommended by the World Health Organization. Artemether, an artemisinin derivative, rapidly reduces parasite load, while lumefantrine and its metabolite desbutyllumfantrine provide a slower but longer-lasting effect due to a long half-life, eliminating remaining parasites and reducing the risk of relapse.