Drug Information

Drug (ID: DG00065) and It's Reported Resistant Information

• Name: Pentamidine
• Synonyms: Lomidine; Nebupent; PENTAM; PNT; Pentacarinat; Pentamide; Pentamidin; Pentamidina; Pentamidinum; Pneumopent; PENTAMIDINE ISETHIONATE; Pentamidina [DCIT]; Pentamidine isetionate; Pentamidine mesylate; MB 800; Pentam 300; Lomidine (TN); MB-800; Nebupent (as isethionate); Pentacarinat (as isethionate); Pentam 300 (as isethionate); Pentamidine (INN); Pentamidinum [INN-Latin]; RP-2512; Nebupent (*Isethionate); Pentacarinat (*Isethionate); Pentam 300 (*Isethionate); Pentamidine Isethionate 2-Hydroxy-Ethanesulfonic Acid;Pentamidine [INN:BAN:DCF]; RP 2512 (*Isethionate); P,p'-(Pentamethylenedioxy)bis[benzamidine]; P,p'-(Pentamethylenedioxy)dibenzamidine; P,p'-(Pentamethylene-dioxy)bis-benzamidine; Benzenecarboximidamide, 4,4'-(1,5-pentanediylbis(oxy))bis-(9CI); 1,3-BIS(4-AMIDINOPHENOXY)PENTANE; 4, 4'-Diamidinodiphenoxypentane; 4,4'-(1,5-Pentanediylbis(oxy))bis-benzenecarboximidamide; 4,4'-(Pentamethylenedioxy)dibenzamide; 4,4'-(Pentamethylenedioxy)dibenzamidine; 4,4'-Diamidino-.alpha.,.omega.-diphenoxypentane; 4,4'-Diamidinodiphenoxypentane; 4,4'-[pentane-1,5-diylbis(oxy)]dibenzenecarboximidamide; 4-[5-(4-Carbamimidoylphenoxy)pentoxy]benzenecarboximidamide
• Indication:
  In total 2 Indication(s)
  Human immunodeficiency virus disease [ICD-11: 1C60-1C62]; Withdrawn from market; [1]
  Fungal infection [ICD-11: 1F29-1F2F]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Pneumonia [ICD-11: CA40]; [1]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  African trypanosomiasis [ICD-11: 1F51]; [2]
• Target: Tryptase alpha/beta-1 (Tryptase); TRYB1_HUMAN; [1]
• Formula: C19H24N4O2
• IsoSMILES: C1=CC(=CC=C1C(=N)N)OCCCCCOC2=CC=C(C=C2)C(=N)N
• InChI: 1S/C19H24N4O2/c20-18(21)14-4-8-16(9-5-14)24-12-2-1-3-13-25-17-10-6-15(7-11-17)19(22)23/h4-11H,1-3,12-13H2,(H3,20,21)(H3,22,23)
• InChIKey: XDRYMKDFEDOLFX-UHFFFAOYSA-N
• PubChem CID: 4735
• ChEBI ID: CHEBI:45081
• TTD Drug ID: D05EAM
• VARIDT ID: DR00085
• DrugBank ID: DB00738

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

African trypanosomiasis [ICD-11: 1F51]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: High-affinity pentamidine transporter (HAPT1) [2]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: African trypanosomiasis [ICD-11: 1F51.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Trypanosoma brucei strain; 5691
• Mechanism Description: While a high level of resistance to diminazene was observed, the resistance factor for pentamidine and the melaminophenyl arsenicals were only two to threefold, significantly less than the arsenical-pentamidine cross-resistant strains generated in the laboratory. Thus, it was clear that at least one additional transporter must contribute to the cross-resistance phenotype. The prime candidate was the high-affinity pentamidine transporter (HAPT1), an activity recorded in bloodstream-form T. brucei using low nanomolar concentrations of [3H]-pentamidine. Melarsoprol also appears to be a substrate for HAPT1 and selection for increased resistance to pentamidine or melarsoprol in Tbat1 null cells led to specific loss of HAPT1 activity.

Key Molecule: Aquaporin 2 (AQP2) [3]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: African trypanosomiasis [ICD-11: 1F51.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: African trypanosomiasis strain; N.A.
• Mechanism Description: The laboratory studies above showed that uptake of both melarsoprol and pentamidine by trypanosomes is under the control of both the P2 adenosine transporter and AQP2. These studies were extended to additional T. b. brucei, T. b. gambiense, and T. b. rhodesiense cross-resistant laboratory-selected strains, which all revealed either chimeric AQP2/3 genes or complete loss of AQP2.

Key Molecule: Aquaporin 2/3 (AQP2/3) [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: African trypanosomiasis [ICD-11: 1F51.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: African trypanosomiasis strain; N.A.
• Mechanism Description: The laboratory studies above showed that uptake of both melarsoprol and pentamidine by trypanosomes is under the control of both the P2 adenosine transporter and AQP2. These studies were extended to additional T. b. brucei, T. b. gambiense, and T. b. rhodesiense cross-resistant laboratory-selected strains, which all revealed either chimeric AQP2/3 genes or complete loss of AQP2.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: NADH dehydrogenase [ubiquinone] flavoprotein 1 (TbAT1) [2]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: African trypanosomiasis [ICD-11: 1F51.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Trypanosoma brucei strain; 5691
• Mechanism Description: Reduced uptake and cross-resistance were apparently explained by the findings that melamine-based arsenicals and diamidines are imported into trypanosomes by the same transporter, and that this transporter is defective in drug-resistant cells. The transporter was called P2 (purine transporter 2) as its physiological substrates are adenine and adenosine, both of which compete with melarsoprol for uptake and can protect trypanosomes from melarsoprol-induced lysis.

ICD-12: Respiratory system diseases

Pneumonia [ICD-11: CA40]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [1]

• Molecule Alteration: Missense mutation; p.D153V
• Resistant Disease: Pneumocystis jirovecii infection [ICD-11: CA40.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pneumocystis jirovecii strain; 42068
• Experiment for Molecule Alteration: PCR amplification and sequence analysis
• Experiment for Drug Resistance: Multivariate analysis of overall survival or disease-free survival assay
• Mechanism Description: Amino acid changes in DHFR may contribute to P. jirovecii emerging drug (Trimethoprim, Pyrimethamine) resistance.

References

• Ref 1: Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis. Antimicrob Agents Chemother. 2004 Nov;48(11):4301-5. doi: 10.1128/AAC.48.11.4301-4305.2004.
• Ref 2: Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story .Trends Parasitol. 2013 Mar;29(3):110-8. doi: 10.1016/j.pt.2012.12.005. Epub 2013 Jan 30. 10.1016/j.pt.2012.12.005
• Ref 3: Melarsoprol Resistance in African Trypanosomiasis .Trends Parasitol. 2018 Jun;34(6):481-492. doi: 10.1016/j.pt.2018.04.002. Epub 2018 Apr 25. 10.1016/j.pt.2018.04.002