Drug Information

Drug (ID: DG00158) and It's Reported Resistant Information

• Name: Loperamide
• Synonyms: Ioperamide; Loperacap; Loperamida; Loperamidum; Kaopectate II; Loperamide Monohydrochloride; Pepto Diarrhea Control; Apo-Loperamide; Diamide (TN); Diarr-Eze; Dimor (TN); Imodium (TN); Imodium A-D Caplets; Loperamida [INN-Spanish]; Loperamide (INN); Loperamide [INN:BAN]; Loperamidum [INN-Latin]; Lopex (TN); Maalox Anti-Diarrheal; Nu-Loperamide; PMS-Loperamide; Pepto (TN); R-18553; Rho-Loperamide
• Indication:
  In total 1 Indication(s)
  Bowel habit change [ICD-11: ME05]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Diarrhea [ICD-11: DA90]; [2]
• Target: Opioid receptor delta (OPRD1); OPRD_HUMAN; [1]
• Formula: C29H33ClN2O2
• IsoSMILES: CN(C)C(=O)C(CCN1CCC(CC1)(C2=CC=C(C=C2)Cl)O)(C3=CC=CC=C3)C4=CC=CC=C4
• InChI: 1S/C29H33ClN2O2/c1-31(2)27(33)29(24-9-5-3-6-10-24,25-11-7-4-8-12-25)19-22-32-20-17-28(34,18-21-32)23-13-15-26(30)16-14-23/h3-16,34H,17-22H2,1-2H3
• InChIKey: RDOIQAHITMMDAJ-UHFFFAOYSA-N
• PubChem CID: 3955
• ChEBI ID: CHEBI:6532
• TTD Drug ID: D0CS2F
• VARIDT ID: DR00171
• DrugBank ID: DB00836

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-13: Digestive system diseases

Diarrhea [ICD-11: DA90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [2]

• Resistant Disease: Diarrhea [ICD-11: DA90.0]
• Molecule Alteration: Activity; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• Experiment for Molecule Alteration: In vitro Caco-2 cell permeability experiments assay
• Experiment for Drug Resistance: Respiration assessments assay
• Mechanism Description: P-glycoprotein is an ATP-dependent efflux pump that transports a wide variety of agents out of cells at the blood-brain barrier, thereby restricting CNS penetration of many drugs, including LOP. TPV is a substrate for and an inducer of P-gp activity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Sensitive Disease: Diarrhea [ICD-11: DA90.0]
• Molecule Alteration: Missense mutation; Haplotype G2677/T3435
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Genotyping assay
• Experiment for Drug Resistance: Assessment of central opioid effects assay
• Mechanism Description: The results support a functional importance of the ABCB1 genetic variants for the pharmacokinetics of loperamide. Highest loperamide plasma concentrations were seen in carriers of haplotype G2677.

ICD-21: Symptoms/clinical signs/unclassified clinical findings

Pain [ICD-11: MG30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [1]

• Sensitive Disease: Pain [ICD-11: MG30.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: ATPase activity assay
• Mechanism Description: P-glycoprotein (Pgp) is a multidrug resistance transporter that limits the penetration of a wide range of neurotherapeutics into the brain including opioids. Pgp-knockout mice had more than a 10-fold higher level of loperamide in their brains than wild-type. Both rats and humans have shown elevated levels of loperamide in the presence of the Pgp-specific inhibitor cyclosporine A.

Finding of gram negative bacteria resistant to antimicrobial drugs [ICD-11: MG50]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Mobilized colistin resistance protein MCR-1 [4]

• Sensitive Disease: severe infection with multidrug-resistant enterobacterales [ICD-11: MG50.C]
• Molecule Alteration: Expression; D1194A+A1182V+Q1106K/R+D1194E/T+S1148A/G
• Mechanism Description: Severe infection with multidrug-resistant Enterobacterales caused by the plasmid-induced colistin resistance gene MCR-1 is a serious public health challenge. In this case, it is necessary and pressing to find a treatment to overcome antibiotic resistance. Here, we investigated the synergistic effect and mechanism of loperamide combined with colistin against MCR-1-positive pathogens. We evaluated the combined effect of loperamide and colistin using the checkerboard method and the time-kill experiment. The results showed that loperamide could enhance the bactericidal ability of colistin, and this combination regimen could completely kill the tested bacteria within 4 h. Subsequently, spectrofluorimetric methods were used to explore the mechanism of loperamide combined with colistin. The results indicated that the mode of action of loperamide combined with colistin was found to involve mechanical disruption of the membrane. Furthermore, molecular simulation and microscale thermophoresis results revealed that loperamide reduced the impact of MCR-1 protein by directly binding to its active site. In addition, the combined regimen of loperamide and colistin effectively reduced the bacterial load in the thighs of mice while increasing the protection rate by 70%. In short, as a potential lead compound, loperamide can enhance the killing effect of colistin on pathogenic Enterobacterales carrying MCR-1 by causing membrane damage and inhibiting MCR-1 protein activity.

References

• Ref 1: A Conformationally Gated Model of Methadone and Loperamide Transport by P-Glycoprotein. J Pharm Sci. 2018 Jul;107(7):1937-1947. doi: 10.1016/j.xphs.2018.02.019. Epub 2018 Feb 28.
• Ref 2: Interaction of ritonavir-boosted tipranavir with loperamide does not result in loperamide-associated neurologic side effects in healthy volunteers. Antimicrob Agents Chemother. 2005 Dec;49(12):4903-10. doi: 10.1128/AAC.49.12.4903-4910.2005.
• Ref 3: Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics. 2003 Nov;13(11):651-60. doi: 10.1097/00008571-200311000-00001.
• Ref 4: Identification of a novel adjuvant loperamide that enhances the antibacterial activity of colistin against MCR-1-positive pathogens in vitro/vivo. Lett Appl Microbiol. 2023 Feb 16;76(2):ovad025.