Drug Information

Drug (ID: DG00077) and It's Reported Resistant Information

• Name: Lumefantrine
• Synonyms: Benflumetol; Coartem; Dl-Benflumelol; Lumefantrine (INN); Lumefantrine [INN:BAN]; (+-)-2,7-Dichloro-9-((Z)-p-chlorobenzylidene)-alpha((dibutylamino)methyl)fluorene-4-methanol; (+-)-2,7-Dichloro-9-((Z)-p-chlorobenzylidene)-alpha-((dibutylamino)methyl)fluorene-4-methanol; 2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]ethanol; 2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylidene]fluoren-4-yl]ethanol; 2-Dibutylamino-1-[2,7-dichloro-9-(4-chloro-benzylidene)-9H-fluoren-4-yl]-ethanol; 2-Dibutylamino-1-{2,7-dichloro-9-[1-(4-chloro-phenyl)-meth-(Z)-ylidene]-9H-fluoren-4-yl}-ethanol
• Indication:
  In total 1 Indication(s)
  Malaria [ICD-11: 1F45]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Astrocytoma [ICD-11: 2F36]; [2]
• Target: Sodium pump subunit alpha-1 (ATP1A1); AT1A1_HUMAN; [1]
• Formula: C30H32Cl3NO
• IsoSMILES: CCCCN(CCCC)CC(C1=CC(=CC\\2=C1C3=C(/C2=C/C4=CC=C(C=C4)Cl)C=C(C=C3)Cl)Cl)O
• InChI: 1S/C30H32Cl3NO/c1-3-5-13-34(14-6-4-2)19-29(35)28-18-23(33)17-27-25(15-20-7-9-21(31)10-8-20)26-16-22(32)11-12-24(26)30(27)28/h7-12,15-18,29,35H,3-6,13-14,19H2,1-2H3/b25-15-
• InChIKey: DYLGFOYVTXJFJP-MYYYXRDXSA-N
• PubChem CID: 6437380
• ChEBI ID: CHEBI:156095
• TTD Drug ID: D06MQM
• INTEDE ID: DR0992
• DrugBank ID: DB06708

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Astrocytoma [ICD-11: 2F36]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Chloroquine resistance transporter (CRT) [3]

• Molecule Alteration: Missense mutation; p.N326S+p.I356T
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Quantitative trait loci (QTL) assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Comparisons of the MEF and HLF responses showed that the Cambodian 803 line, as for LUM, was less susceptible than Ghanaian GB4 to these drugs: the geometric mean EC50s of 803 relative to GB4 were 2.9-fold greater with MEF and 4.6-fold greater with HLF, whereas these were 2.0-fold greater with CQ and 1.7-fold reduced w.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Drug Resistance: HRP-2 ELISA assay
• Mechanism Description: Isolates with multiple pfmdr1 copies had significantly higher IC50s against OZ78, OZ277, MQ, and LUM. In contrast, no significant differences in IC50s between isolates with single and multiple pfmdr1 copy numbers were observed for the other test compounds.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [1]

• Molecule Alteration: Missense mutation; p.N86Y
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: MIP probes and PCR sequencing assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: Despite the availability of few mutant parasites for comparison, the PfMDR1 Asn86Tyr substitution appeared to be associated with increased susceptibility to lumefantrine and mefloquine, as seen prev.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]

• Molecule Alteration: Missense mutation; p.N86+p.Y184
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum isolates; 5833
• Experiment for Molecule Alteration: Quantitative trait loci (QTL) assay
• Experiment for Drug Resistance: SYBR Green I detection assay
• Mechanism Description: The geometric mean LUM EC50 of 803 was 5.8-fold greater than GB4 (3.21 nM, 95% Confidence Interval 2.80-3.66 nM vs. 0.55 nM, 95% CI 0.46-0.67 nM, respectively). The Cambodian 803 line, as for LUM, was less susceptible than Ghanaian GB4 to these drugs: the geometric mean EC50s of 803 relative to GB4 were 2.9-fold greater with MEF and 4.6-fold greater with HLF, whereas these were 2.0-fold greater with CQ and 1.7-fold reduced with DHA.

Key Molecule: Chloroquine resistance transporter (CRT) [4]

• Molecule Alteration: Missense mutation; p.K76T
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Nested PCR
• Mechanism Description: Both in vitro and molecular surveillance studies have associated CQ resistance mainly with the pfcrt 76T allele, but also with pfmdr1 86Y and 184F alleles. Pfcrt 76T and pfmdr1 86Y mutant alleles have also been reported to decrease P. falciparum susceptibility to amodiaquine but increase parasite sensitivity to dihydroartemisinin, lumefantrine and mefl.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]

• Molecule Alteration: Missense mutation; p.N86Y
• Sensitive Disease: Malaria [ICD-11: 1F45.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Plasmodium falciparum strains; 5833
• Experiment for Molecule Alteration: Nested PCR
• Mechanism Description: Both in vitro and molecular surveillance studies have associated CQ resistance mainly with the pfcrt 76T allele, but also with pfmdr1 86Y and 184F alleles. Pfcrt 76T and pfmdr1 86Y mutant alleles have also been reported to decrease P. falciparum susceptibility to amodiaquine but increase parasite sensitivity to dihydroartemisinin, lumefantrine and mefl.

References

• Ref 1: Evolution of Multidrug Resistance in Plasmodium falciparum: a Longitudinal Study of Genetic Resistance Markers in the Greater Mekong Subregion. Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0112121. doi: 10.1128/AAC.01121-21. Epub 2021 Sep 13.
• Ref 2: Ex vivo activity of endoperoxide antimalarials, including artemisone and arterolane, against multidrug-resistant Plasmodium falciparum isolates from Cambodia. Antimicrob Agents Chemother. 2014 Oct;58(10):5831-40. doi: 10.1128/AAC.02462-14. Epub 2014 Jul 21.
• Ref 3: Evidence for linkage of pfmdr1, pfcrt, and pfk13 polymorphisms to lumefantrine and mefloquine susceptibilities in a Plasmodium falciparum cross. Int J Parasitol Drugs Drug Resist. 2020 Dec;14:208-217. doi: 10.1016/j.ijpddr.2020.10.009. Epub 2020 Oct 27.
• Ref 4: Prevalence of chloroquine and antifolate drug resistance alleles in Plasmodium falciparum clinical isolates from three areas in Ghana. AAS Open Res. 2018 Dec 3;1:1. doi: 10.12688/aasopenres.12825.2. eCollection 2018.