PENTAMIDINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C19H24N4O2
Molecular Weight	340.4195
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC(=N)C1=CC=C(OCCCCCOC2=CC=C(C=C2)C(N)=N)C=C1

InChI

InChIKey=XDRYMKDFEDOLFX-UHFFFAOYSA-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)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf
Curator's Comment: description was created based on several sources, including: http://www.drugbank.ca/drugs/DB00738 https://en.wikipedia.org/wiki/Pentamidine

Pentamidine (formulated as a salt, pentamidine diisethionate or dimesilate) is an antimicrobial medication given for prevention and treatment of pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a severe interstitial type of pneumonia often seen in patients with HIV infection. The drug is also the mainstay of treatment for stage I infection with Trypanosoma bruceigambiense (West African trypanosomiasis). Pentamidine is also used as a prophylactic against PCP in patients receiving chemotherapy and in some patients who have undergone organ transplantation, as they also have a depressed immune system as a direct side-effect of the drugs used. The mortality of untreated PCP is very high. Additionally, pentamidine has good clinical activity in treating leishmaniasis, and yeast infections caused by the organism Candida albicans. Pentamidine is also used as a prophylactic antibiotic for children undergoing treatment for leukemia. Studies suggest that the pentamidine isethionate interferes with microbial nuclear metabolism by inhibition of DNA, RNA, phospholipid and protein synthesis. However, the mode of action is not fully understood.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
tRNA (cytosine(38)-C(5))-methyltransferase 6 Target ID: O14717 Gene ID: 1787.0 Gene Symbol: TRDMT1 Target Organism: Homo sapiens (Human) Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2275129/	Binding Agent 1037		204.4 µM [EC50]
DNA 241 Target ID: CHEMBL2366046 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2ad9d3c-b6c3-4f70-87e0-722a8ff94ccb#nlm34090-1	Inhibitor 8146

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pneumocystis jiroveci pneumonia (PJP) in high-risk, HIV-infected patients 6 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf	Preventing		Approved 8307	NEBUPENT Approved Use Pentamidine Launch Date 4.82112012E11

C_max

Value	Dose	Analyte	Population
751 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8056699	3.9 mg/kg 1 times / day multiple, intravenous dose: 3.9 mg/kg route of administration: Intravenous experiment type: MULTIPLE co-administered:	PENTAMIDINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
18.8 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf	4 mg/kg 1 times / day multiple, irrigation dose: 4 mg/kg route of administration: Irrigation experiment type: MULTIPLE co-administered:	PENTAMIDINE unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
612 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf	4 mg/kg single, intravenous dose: 4 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	PENTAMIDINE unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
6734 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8056699	3.9 mg/kg 1 times / day multiple, intravenous dose: 3.9 mg/kg route of administration: Intravenous experiment type: MULTIPLE co-administered:		PENTAMIDINE blood	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
6.4 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf	4 mg/kg single, intravenous dose: 4 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		PENTAMIDINE unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1600 mg single, intravenous Overdose Dose: 1600 mg Route: intravenous Route: single Dose: 1600 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	unhealthy, 17 n = 1 Health Status: unhealthy Condition: Pneumonia due to Pneumocystis carinii Age Group: 17 Population Size: 1 Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	Other AEs: Impaired renal function, Hepatic impairment... Other AEs: Impaired renal function Hepatic impairment Hypotension Cardiopulmonary arrest Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display
600 mg 1 times / month multiple, respiratory Highest studied dose Dose: 600 mg, 1 times / month Route: respiratory Route: multiple Dose: 600 mg, 1 times / month Sources: https://pubmed.ncbi.nlm.nih.gov/8750367 Page: p.1167	unhealthy, 37.9 ± 7.5 n = 76 Health Status: unhealthy Condition: Pneumonia due to Pneumocystis carinii Age Group: 37.9 ± 7.5 Sex: M+F Population Size: 76 Sources: https://pubmed.ncbi.nlm.nih.gov/8750367 Page: p.1167	Sources: https://pubmed.ncbi.nlm.nih.gov/8750367 Page: p.1167
300 mg 1 times / month multiple, respiratory Recommended Dose: 300 mg, 1 times / month Route: respiratory Route: multiple Dose: 300 mg, 1 times / month Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf Page: p.6	unhealthy Health Status: unhealthy Condition: Pneumonia due to Pneumocystis carinii Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf Page: p.6	Disc. AE: Acute pancreatitis... AEs leading to discontinuation/dose reduction: Acute pancreatitis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019887s014lbl.pdf Page: p.6
4 mg/kg 1 times / day multiple, intramuscular Recommended Dose: 4 mg/kg, 1 times / day Route: intramuscular Route: multiple Dose: 4 mg/kg, 1 times / day Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	unhealthy Health Status: unhealthy Condition: Pneumonia due to Pneumocystis carinii Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	Disc. AE: Hypotension, Hypoglycemia... Other AEs: Extravasation, Injection site ulceration... AEs leading to discontinuation/dose reduction: Hypotension (grade 3-5) Hypoglycemia (grade 5) Acute pancreatitis (grade 5) Cardiac arrhythmias (grade 5) Cardiac arrhythmias (grade 5) Other AEs: Extravasation Injection site ulceration Injection site necrosis Slough injection site Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display
4 mg/kg 1 times / day multiple, intravenous Recommended Dose: 4 mg/kg, 1 times / day Route: intravenous Route: multiple Dose: 4 mg/kg, 1 times / day Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	unhealthy Health Status: unhealthy Condition: Pneumonia due to Pneumocystis carinii Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display	Disc. AE: Hypotension, Hypoglycemia... Other AEs: Extravasation, Injection site ulceration... AEs leading to discontinuation/dose reduction: Hypotension (grade 3-5) Hypoglycemia (grade 5) Acute pancreatitis (grade 5) Cardiac arrhythmias (grade 5) Cardiac arrhythmias (grade 5) Other AEs: Extravasation Injection site ulceration Injection site necrosis Slough injection site Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=cc2b635e-4840-4dc3-a177-5484371680e8&type=display

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
Kir4.1 6	OCT1 317 P-gp 1491 MRP transporters 10

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
Kir4.1 6	inhibitor 3185 Sources: https://pubmed.ncbi.nlm.nih.gov/28993158/	yes [IC50 0.097 uM]
BCRP 751	activator 208 Sources: https://pubmed.ncbi.nlm.nih.gov/22200378/	yes

Drug as victim

Target	Modality	Activity
MRP transporters 10	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/19261919/	yes
OCT1 317	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/28362799/	yes
P-gp 1491	substrate 3264 Sources: https://pubmed.ncbi.nlm.nih.gov/19261919/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:45081	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:45081
ChemicalBook	CB4476092	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4476092
MolPort	MolPort-001-792-506	https://www.molport.com/shop/molecule-link/MolPort-001-792-506
ZINC	ZINC000001530775	http://zinc15.docking.org/substances/ZINC000001530775
eMolecules	1012733	https://www.emolecules.com/cgi-bin/more?vid=1012733

PubMed

Title	Date	PubMed
Efficacy of trimethoprim and sulfamethoxazole in the prevention and treatment of Pneumocystis carinii pneumonitis.	1974 Mar	4365115
[Kidney failure during treatment of T. rhodesiense trypanosomiasis with pentamidin].	1977	610624
[Nephrotoxic effect of pentamidine in the treatment of interstitial pneumonia in 2 children with acute lymphoblastic leukemia].	1979 Dec	294951
Visceral leishmaniasis unresponsive to antimonial drugs. II. Response to high dosage sodium stibogluconate or prolonged treatment with pentamidine.	1985	3006295
Pentamidine treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Association with acute renal failure and myoglobinuria.	1985 Dec	3878136
Extrapyramidal symptoms in AIDS patients given low-dose metoclopramide or chlorpromazine.	1985 Nov 23	2865637
Sciatic nerve damage associated with pentamidine.	1985 Oct	2996869
Pentamidine-associated hypotension and route of administration.	1985 Sep	4026103
Pentamidine and renal toxicity.	1985 Sep 12	4022063
Hypoglycemic coma from pentamadine in an AIDS patient.	1986 Jul	3487333
Pentamidine and hematuria.	1986 Jul	3487266
Pentamidine-induced hypoglycemia in patients with the acquired immune deficiency syndrome.	1986 Mar	3485027
Adverse reactions associated with pentamidine isethionate in AIDS patients: recommendations for monitoring therapy.	1986 Nov	3490958
Torsade de pointes during administration of pentamidine isethionate.	1987 Sep	3499072
Aggressive psychosis in AIDS patient on high-dose steroids.	1987 Sep 26	2888983
Tremor induced by trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome (AIDS).	1988 Jul 1	2967659
Cationic antitrypanosomal and other antimicrobial agents in the therapy of experimental Pneumocystis carinii pneumonia.	1988 Jun	3137861
Ventricular tachycardia due to pentamidine isethionate.	1988 May	3364459
Torsades de pointes during intravenous pentamidine isethionate therapy.	1989 Jan 15	2783374
Renal insufficiency with nebulised pentamidine.	1989 Oct 28	2572780
Nephrotoxicity and hyperkalemia in patients with acquired immunodeficiency syndrome treated with pentamidine.	1989 Sep	2773964
Pentamidine-induced torsades de pointes in a renal transplant recipient with Pneumocystis carinii pneumonia.	1990 Apr	2321077
Acute, rapidly progressive renal failure with simultaneous use of amphotericin B and pentamidine.	1990 Mar	2334159
Pentamidine-induced facial numbness.	1991 Apr	2032443
Pentamidine-associated nephrotoxicity and hyperkalemia in patients with AIDS.	1991 Nov	1763529
Inhibition of topoisomerases from Pneumocystis carinii by aromatic dicationic molecules.	1991 Nov-Dec	1667935
[Infantile visceral leishmaniasis in Morocco. A review of 67 cases managed at the Rabat Hospital for children (1979-1988)].	1991 Sep	1659303
High pentamidine levels associated with hypoglycemia and azotemia in a patient with Pneumocystis carinii pneumonia.	1992 Aug	1424505
Prolonged recurrence of pentamidine-induced torsades de pointes.	1992 Nov	1477438
Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs.	1992 Sep	1416885
New agents active against Mycobacterium avium complex selected by molecular topology: a virtual screening method.	2004 Jan	14645324
Search of chemical scaffolds for novel antituberculosis agents.	2005 Apr	15809316
A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system.	2005 Feb	15342952
Detection of immunotoxicity using T-cell based cytokine reporter cell lines ("Cell Chip").	2005 Jan 15	15588918
Early-onset pentamidine-associated second-degree heart block and sinus bradycardia: case report and review of the literature.	2005 Jun	15927910
Protein trafficking abnormalities: a new mechanism in drug-induced long QT syndrome.	2005 May	15711590
Pentamidine is an antiparasitic and apoptotic drug that selectively modifies ubiquitin.	2005 Oct	17191940
In vitro selection and in vivo efficacy of piperazine- and alkanediamide-linked bisbenzamidines against Pneumocystis pneumonia in mice.	2006 Jul	16801410
[Cutaneous leishmaniasis--an import from Belize].	2007	17987367
Cellulose biosynthesis pathway is a potential target in the improved treatment of Acanthamoeba keratitis.	2007 May	17225099
Using the zebrafish lateral line to screen for ototoxicity.	2008 Jun	18408970
Pentamidine dosage: a base/salt confusion.	2008 May 28	18509543
Identification of human Ether-à-go-go related gene modulators by three screening platforms in an academic drug-discovery setting.	2010 Dec	21158687
Bisbenzamidines as antifungal agents. are both amidine functions required to observe an anti-Pneumocystis carinii activity?	2010 Jun 11	20657441
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011 Jul 14	21599003
The pharmacological profile of brain liver intestine Na+ channel: inhibition by diarylamidines and activation by fenamates.	2011 Nov	21828194
Synthetic chromanol derivatives and their interaction with complex III in mitochondria from bovine, yeast, and Leishmania.	2011 Oct 17	21809846
Synthesis and antiprotozoal activities of benzyl phenyl ether diamidine derivatives.	2013 Sep	23871911
Utilization of human nuclear receptors as an early counter screen for off-target activity: a case study with a compendium of 615 known drugs.	2015 Jun	25752796
Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis.	2015 May 18	25811541

Patents

Sample Use Guides

In Vivo Use Guide

The recommended adult dosage is 300 mg once every four weeks administered via the Respirgard® II nebulizer. The dose should be delivered until the nebulizer chamber is empty (approximately 30 to 45 minutes). The flow rate should be 5 to 7 liters per minute from a 40 to 50 pounds per square inch (PSI) air or oxygen source. Alternatively, a 40 to 50 PSI air compressor can be used with flow limited by setting the flowmeter at 5 to 7 liters per minute or by setting the pressure at 22 to 25 PSI. Low pressure (less than 20 PSI) compressors should not be used.

Route of Administration: Irrigation

In Vitro Use Guide

Pentamidine was found to be active against T. whipplei strains both in axenic medium and in cell culture, with minimum inhibitory concentration ranges of 0.125-0.25mg/L.

Name

Type

Language

PENTAMIDINE

Official Name

English

NSC-9921

Code

English

RP-2512 FREE BASE

Code

English

PENTAM 300

Brand Name

English

MB-800

Code

English

PENTAMIDINE [VANDF]

Common Name

English

4,4'-(PENTAMETHYLENEDIOXY)DIBENZAMIDINE

Systematic Name

English

Pentamidine [WHO-DD]

Common Name

English

RP-2512

Code

English

RP 2512 FREE BASE

Code

English

MP-601205

Common Name

English

PENTAMIDINE [MI]

Common Name

English

MB 800 FREE BASE

Code

English

pentamidine [INN]

Common Name

English

MB-800 FREE BASE

Code

English

MB-800 (AS ISETHIONATE)

Code

English

PENTAMIDINE [HSDB]

Common Name

English

Classification Tree Code System Code

WHO-ATC

P01CX01