Disease Information

General Information of the Disease (ID: DIS00129)

• Name: Diarrhea
• ICD: ICD-11: DA90

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Loperamide

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) [1]

• Resistant Disease: Diarrhea [ICD-11: DA90.0]
• Molecule Alteration: Activity; Up-regulation
• Resistant Drug: Loperamide
• 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) [2]

• Sensitive Disease: Diarrhea [ICD-11: DA90.0]
• Molecule Alteration: Missense mutation; Haplotype G2677/T3435
• Sensitive Drug: Loperamide
• 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.

Zithromax

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S rRNA (cytidine-2'-O)-methyltransferase TlyA (TLYA) [3]

• Resistant Disease: Traveler's diarrhea [ICD-11: DA90.1]
• Molecule Alteration: Missense mutation; p.A2075G
• Resistant Drug: Zithromax
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Campylobacter jejuni isolates; 197
• In Vitro Model: Campylobacter jejuni ATCC 33560; 197
• Experiment for Molecule Alteration: Gene sequencing assay
• Experiment for Drug Resistance: E-test assay
• Mechanism Description: Point mutation occurred on the 23S rRNA gene at the A2075G transitions, and the number of mutated gene copies was proportional to azithromycin resistance.

References

• Ref 1: 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 2: 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 3: Determination of azithromycin heteroresistant Campylobacter jejuni in traveler's diarrhea .Gut Pathog. 2019 May 6;11:19. doi: 10.1186/s13099-019-0301-1. eCollection 2019. 10.1186/s13099-019-0301-1