In WM9, DU145, C4-2, Hey, WM480, and A549 cells, pentamidine administration (0–10 µg/mL; 6 days) reduces cancer cell proliferation in a concentration-dependent manner [1]. It has been established that pentamidine isethionate is cytotoxic to Leishmania infantum promastigotes. Pentamidine isethionate was 60 times more leishmanicidal than cisplatin after 72 hours of incubation. Compared to cisplatin, pentamidine isethionate causes a greater amount of programmed cell death (PCD), which is linked to suppression of DNA synthesis and cell cycle arrest in the G2/M phase. When pentamidine isethionate is bound to calf thymus DNA (CT-DNA), the DNA double helix undergoes structural changes that align with the B-to-A transition. The protein's β-sheet composition increases by 6% as a result of the interaction between pentamidine isethionate and ubiquitin [2].

The treatment of athymic nude mice with pentamidine (0.25 mg/mouse; intramuscular injection; every 2 days; for 4 weeks) can effectively limit the growth of WM9 human melanoma [1].

Cell Viability Assay[1]
Cell Types: WM9, DU145, C4-2, Hey, WM480 and A549 Cell
Tested Concentrations: 0-10 µg/mL
Incubation Duration: 6 days
Experimental Results: Growth of all six cell lines in culture Inhibited in a concentration-dependent manner, with complete growth inhibition of the cell line at 10 µg/mL.

Animal/Disease Models: Athymic nude mice (6 weeks old) injected with WM9 cells [1]
Doses: 0.25mg/mouse
Route of Administration: intramuscularinjection; once every 2 days; for 4 consecutive weeks
Experimental Results: Dramatically inhibited WM9 human melanoma Growth in nude mice.

Absorption, Distribution and Excretion
Absorbed poorly through the gastrointestinal tract and is usually administered parenterally.
Pentamidine isethionate is fairly well absorbed from parenteral sites of admin despite the formation of sterile abscesses that may occur after its used. Following a single intravenous dose, the drug disappears from plasma with an apparent half-life of several min to a few hours; this is followed by a slower distribution phase and a prolonged elimination phase lasting from weeks to months. Patients with African trypanosomiasis exhibit marked interindividual variations in pharmacokinetic parameters. Their mean system plasma clearance after a single dose is about 1120 mL/min, but the volume of distribution is about 25,000 L, a finding that accounts for the prolonged average elimination half-life of about 12 days ... The renal clearance of pentamidine averages only about 2% to 11% of its systemic clearance ... but whether the drug is metabolized or excreted in bile ... is unknown. In patients receiving multiple injections of the drug over a 13-day period for treatment of pneumocystosis, drug accumulation occurs such that no steady-state plasma concn is attained ... /Pentamidine isethionate/
... After multiple parenteral doses, the liver, kidney, adrenal, and spleen of patients with AIDS contain the highest concn of drug, whereas only traces are found in the brain ... Lungs of such patients contain intermediate but therapeutic concn after 5 daily doses of 4 mg of base/kg. Higher pulmonary concn should be achieved by inhalation of pentamidine aerosols for prophylaxis or as adjunctive treatment for mild to moderate Pneumocystis carinii pneumonia; delivery of drug by this route results in little systemic absorption and decreased toxicity compared with intravenous admin in both adults and children. The actual dose delivered to the lungs depends on both the size of particles generated by the nebulizer and the patient's ventilatory patterns. /Pentamidine isethionate/
Aerosolized pentamidine produces concentrations approximately 10 to 100 times higher in the lungs than would a comparable dose of IV pentamidine.
Systemic absorption of inhaled pentamidine is minimal, with serum pentamidine concentrations less than 20 nanograms per mL after a nebulized dose of 4 mg/kg in most cases (versus 612 nanogram per mL after a single IV dose of 4 mg/kg). Peak systemic absorption occurs at, or near, completion of inhalation therapy.
For more Absorption, Distribution and Excretion (Complete) data for PENTAMIDINE (14 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic.
By using high-performance liquid chromatography, the in vitro conversion of pentamidine to the corresponding amidoximes (N-hydroxypentamidine and N,N'-dihydroxypentamidine) was studied in supernatants of rat liver homogenate centrifuged at 9,000 x g. The presence of the two amidoxime peaks in chromatograms was confirmed by liquid secondary ion mass spectrometry and by unequivocal synthesis of the suspected metabolites. The metabolic reactions were found to be catalyzed by the cytochrome P-450 system (mixed-function oxidases). The formation of the monohydroxylated product was found to have a Km of 0.48 mM and a Vmax of 29.50 pmol/min per mg of protein, while the dihydroxylated metabolite had a Km of 0.73 mM and a Vmax of 4.10 pmol/min per mg of protein. ...
The antiprotozoal/antifungal drug pentamidine [1,5-bis(4-amidinophenoxy)pentane] has been recently shown to be metabolized by rat liver fractions to at least six putative metabolites as detected by high-performance liquid chromatography. ... In this study, the two major microsomal metabolites have been identified as the 2-pentanol and 3-pentanol analogs of pentamidine [1,5-di(4-amidinophenoxy)-2-pentanol; and 1,5-bis(4-amidinophenoxy)-3-pentanol]. As well, a seventh putative metabolite has been discovered and identified as para-hydroxybenzamidine, a fragment of the original drug. ... the cytochromes P-450 have been demonstrated as the enzyme system responsible for pentamidine metabolism ... the mixed-function oxidases readily convert pentamidine to hydroxylated metabolites, but exactly which isozyme(s) of cytochrome P-450 is responsible is not clear.
The antiprotozoal drug pentamidine [1,5-bis(4'-amidinophenoxy)pentane] has been previously shown to be metabolized by rat liver microsomes, and five of the seven putative primary metabolites have been identified. With the synthesis and identification of 5-(4'-amidinophenoxy)pentanoic acid and 5-(4'-amidinophenoxy)-1-pentanol as the remaining two metabolites, the primary metabolism of pentamidine in rats appears fully characterized. ... Isolated, perfused rat livers were used with [14C]pentamidine to identify secondary metabolites. Only two novel radioactive peaks were detected by HPLC analysis of perfused liver samples. The treatment of liver samples with sulfatase or beta-glucuronidase resulted in the reduction or elimination of these peaks and gave rise to peaks identified as para-hydroxybenzamidine and 5-(4'-amidinophenoxy)pentanoic acid. It was concluded from these results that only these two primary metabolites were conjugated with sulfate or glucuronic acid.
Pentamidine /is a substrate for/ human liver microsomal P450 enzyme CYP2C19. /From table/
Hepatic.
Half Life: 9.1-13.2 hours

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Biological Half-Life
9.1-13.2 hours
Intramuscular: 9.1 to 13.2 hours. Intravenous: Approximately 6.5 hours. Terminal half-life: 2 to 4 weeks. Renal function impairment: Pentamidine half-life may be prolonged in patients with renal dysfunction ; however, no correlation between renal function and plasma clearance of pentamidine has been found.

Toxicity Summary
The mode of action of pentamidine is not fully understood. It is thought that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids, and proteins.

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Hepatotoxicity
Pentamidine has been associated with serum aminotransferase elevations in 9% to 15% of patients receiving 2 to 3 weeks of therapy for pneumocystis pneumonia. Clinically apparent liver injury has also been reported with its use, but always in association with multiple other severe complications, such as respiratory or renal failure and pancreatitis. The onset of injury is within days of starting therapy and is characterized by acute hepatic necrosis, marked elevations in serum aminotransferase levels, rapid development of prolongation of prothrombin time and minimal or no jaundice. Recovery is typically rapid and usually complete.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Protein Binding
69%

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Interactions
Since nephrotoxic effects may be additive, the concurrent or sequential use of pentamidine isethionate and other drugs with similar toxic potentials such as aminoglycosides, amphotericin B, capreomycin, colistin, cisplatin, foscarnet, methoxyflurane, polymyxin B, or vancomycin should be closely monitored or avoided, if possible.
Concurrent use of other nephrotoxic medications with pentamidine may increase the potential for nephrotoxicity; renal function determinations, dosage reductions, and/or dosage interval adjustments may be required.
Renal side-effects are frequently observed after parenteral administration of pentamidine. In this study in a rat model, the nephrotoxicity was assessed by measuring urinary loss of tubular cells, malate dehydrogenase activity and creatinine clearance. In addition, we studied the influence of other nephrotoxins such as tobramycin, amphotericin B and cyclosporin on the pentamidine-associated nephrotoxicity and proved the possibilities of reducing this toxicity by coadministration with other drugs. The tubular toxicity of pentamidine (1, 10 or 20 mg/kg daily) is dose-related and reversible. The toxicity can be reduced by coadministration of fosfomycin (1 x 500 or 2 x 250 mg/kg daily) and D-glucaro-1,5-lactam (2 x 5 mg/kg daily) and enhanced by tobramycin (2 x 2.5 mg/kg daily), amphotericin B (1 mg/kg daily) and cyclosporin (10 mg/kg daily). Furthermore, an increase in the creatinine clearance in pentamidine-treated rats can be obtained with both verapamil (2 x 1.5 mg/kg daily) and enalapril (5 mg/kg daily).
Concurrent use /of foscarnet/ with pentamidine may result in severe, but reversible, hypocalcemia, hypomagnesemia, and nephrotoxicity.
For more Interactions (Complete) data for PENTAMIDINE (8 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse subcutaneous 120 mg/kg
LD50 Mouse intraperitoneal 63 mg/kg
LD50 Mouse IV 15 mg/kg

[1]. Pentamidine is an inhibitor of PRL phosphatases with anticancer activity. Mol Cancer Ther. 2002 Dec;1(14):1255-64.

[2]. Pentamidine is an antiparasitic and apoptotic drug that selectively modifies ubiquitin. Chem Biodivers, 2005. 2(10): p. 1387-400.

[3]. Pentamidine: a review. Rev Infect Dis. 1985 Sep-Oct;7(5):625-34.

[4]. Pentamidine: a drug to consider re-purposing in the targeted treatment of multi-drug resistant bacterial infections? J Lab Precis Med 2017;2:49.

Therapeutic Uses
Pentamidine is indicated in the treatment of Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS). Sulfamethoxazole and trimethoprim combination is considered to be the primary agent for PCP in patients who can tolerate it. /Included in US product labeling/
Pentamidine is used as a secondary agent in the treatment of visceral leishmaniasis (kala-azar) caused by Leishmania donovani. Stibogluconate sodium, a pentavalent antimony derivative, is considered to be the primary agent for visceral leishmaniasis. /NOT included in US product labeling/
Pentamidine is used as a secondary agent in the treatment of cutaneous leishmaniasis caused by Leishmania tropica, L. major, L. mexicana, L. aethiopica, L. peruviana, L. guyanensis, and L. braziliensis. Stibogluconate sodium, a pentavalent antimony derivative, is considered to be the primary agent for cutaneous leishmaniasis. /NOT included in US product labeling/
Aerosolized pentamidine is indicated in both secondary prophylaxis (patients who have already had at least one episode of Pneumocystis carinii pneumonia) and primary prophylaxis (HIV-infected patient with a CD4 lymphocyte count less than or equal to 200 cells per cubic millimeter) of Pneumocystis carinii pneumonia. /Included in US product labeling/
For more Therapeutic Uses (Complete) data for PENTAMIDINE (12 total), please visit the HSDB record page.

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Drug Warnings
Fatalities due to severe hypotension, hypoglycemia, acute pancreatitis and cardiac arrhythmias have been reported in patients treated with pentamidine isethionate, both by the IM and IV routes. Severe hypotension may result after a single IM or IV dose and is more likely with rapid IV administration. The administration of the drug should, therefore, be limited to the patients in whom Pneumocystis carinii has been demonstrated. Patients should be closely monitored for the development of serious adverse reactions.
Nephrotoxicity reportedly occurs in at least 25% of patients with pneumocystis pneumonia receiving parenteral pentamidine isethionate. Pentamidine-induced nephrotoxicity is manifested by an increase in serum creatinine concentration and/or BUN, usually developing gradually and appearing during the second week of therapy with the drug. Azotemia also has been reported. Renal insufficiency is usually mild to moderate in severity and reversible following discontinuance of pentamidine; however, acute renal failure (e.g., serum creatinine concentration greater than 6 mg/dL) or severe renal insufficiency requiring discontinuance of the drug may occur occasionally. Limited evidence suggests that nephrotoxicity and hyperkalemia both may occur more frequently in patients with AIDS than in other patients treated with parenteral pentamidine; hyperkalemia has been severe in some patients. Rarely, pentamidine-induced acute renal failure has been associated with myoglobinuria or gross hematuria. The risk and degree of pentamidine-induced renal impairment may be increased in the presence of dehydration or by concomitant use of other nephrotoxic drugs. Acute renal failure has been reported in at least 1 patient receiving pentamidine inhalation therapy; flank pain and nephritis also have been reported occasionally in patients receiving the aerosolized drug by oral inhalation via nebulizer.
Cardiorespiratory arrest (following rapid IV injection), ventricular tachycardia, atypical ventricular tachycardia (torsade de pointes), ECG abnormalities, and facial flushing have also been reported in patients receiving parenteral pentamidine. The risk of hypotensive reactions following IM or IV administration of pentamidine isethionate has not been directly compared, but some data suggest that there is no difference in the frequency of these reactions following either route of administration when IV infusions of the drug are administered over a period of at least 60 minutes. Hypotensive reactions may be particularly likely to occur following rapid IV injection or infusion. To minimize the risk of this adverse effect when pentamidine isethionate is administered IV, infusions of the drug should be given over a period of 60-120 minutes. However, hypotension, which was not ameliorated by adjustment of the infusion rate, persisted beyond completion of the infusion, and required volume expansion for correction, has been reported in some patients. Hypotension, hypertension, tachycardia, palpitations, syncope, dizziness, light-headedness, diaphoresis, cerebrovascular accident, vasodilatation, and vasculitis have been reported occasionally in patients receiving orally inhaled pentamidine.
Since pentamidine has become commercially available, there is renewed interest in using it as the initial treatment for Pneumocystis carinii pneumonia in AIDS patients. /The authors/ reviewed the use of pentamidine in 24 patients with Pneumocystis carinii pneumonia to gain information on the prevalence and severity of adverse effects from this drug. Twenty out of twenty-four patients (83 percent) experienced some kind of adverse effect. Hepatic abnormalities (58 percent), nausea and vomiting (46 percent), hypoglycemia (33 percent), azotemia (25 percent), and pain at the injection site (25 percent) were the most frequently seen effects.
For more Drug Warnings (Complete) data for PENTAMIDINE (25 total), please visit the HSDB record page.

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Pharmacodynamics
Pentamidine is an antiprotozoal agent. It is an aromatic diamidine, and is known to have activity against Pneumocystis carinii. The exact nature of its antiprotozoal action is unknown. in vitro studies with mammalian tissues and the protozoan Crithidia oncopelti indicate that the drug interferes with nuclear metabolism producing inhibition of the synthesis of DNA, RNA, phospholipids and proteins. Little is known about the drug's pharmacokinetics. The medication is also useful in Leishmaniasis and in prophylaxis against sleeping sickness caused by Trypanosoma brucei gambiense. Hydration before treatment lessens the incidence and severity of side effects, which include liver or kidney dysfunction, hypertension, hypotension, hypoglycemia, hypocalemia, leukopenia, thrombcytopenia, anemia, and allergic reaction. It is generally well-tolerated.

C19H24N4O2

340.41946

340.189

100-33-4

Pentamidine isethionate;140-64-7;Pentamidine dihydrochloride;50357-45-4;Pentamidine dimesylate;6823-79-6

4735

White to off-white solid powder

1.2±0.1 g/cm3

539.4±60.0 °C at 760 mmHg

186ºC (dec.)

280.0±32.9 °C

0.0±1.4 mmHg at 25°C

1.593

2.47

4

4

10

25

376

0

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)

4-[5-(4-carbamimidoylphenoxy)pentoxy]benzenecarboximidamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)