Pentoxifylline suppresses cell growth in a dose-dependent manner (0.1–50 mM; 24-48 hours) [3]. In MDA-MB-231 cells, pentoxifylline (0.5 mM; 12-36 hours) decreases autophagy and promotes apoptosis [3]. In MDA-MB-231 cells, pentoxifylline (0.5 mM; 12-36 hours) promotes autophagy [3]. The G0/G1 phase of the cell cycle is blocked by pentoxifylline (0.5 mM; 24-48 hours) [3]. Elevated LC3-II/LC3 ratio is brought on by pentoxifylline [3].

In rats exposed to transitory global ischemia, pentoxifylline (200 mg/kg; i.p.) exerts a protective effect and lessens cognitive damage [4].

Cell proliferation assay[3]
Cell Types: MDA-MB-231 Cell
Tested Concentrations: 0.1 mM, 1 mM, 5 mM, 10 mM, 50 mM
Incubation Duration: 24 hrs (hours), 48 hrs (hours)
Experimental Results: Inhibition of cell proliferation in a dose-dependent manner.

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Apoptosis analysis[3]
Cell Types: MDA-MB-231 Cell
Tested Concentrations: 0.5 mM
Incubation Duration: 12 hrs (hours), 24 hrs (hours), 36 hrs (hours)
Experimental Results: Induction of apoptosis.

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Autophagy assay [3]
Cell Types: MDA-MB-231 Cell
Tested Concentrations: 0.5 mM
Incubation Duration: 24 hrs (hours), 48 hrs (hours)
Experimental Results: Approximately 20-28% of autophagy was induced.

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Cell cycle analysis [3]
Cell Types: MDA-MB-231 Cell
Tested Concentrations: 0.5 mM
Incubation Duration: 24 hrs (hours), 48 hrs (hours)
Experimental Results: Induced G0/G1 phase arrest.

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Western Blot Analysis[3]
Cell Types: MDA-MB-231 Cell
Tested Concentrations: 0.5 mM
Incubation Duration: 24 hrs (hours), 48 hrs (hours)
Experimental Results: Induction of high LC3-II/LC3 ratio.

Animal/Disease Models: Adult male Wistar rats, 12-13 weeks old (250-300 g) [4]
Doses: 200 mg/kg
Route of Administration: intraperitoneal (ip) injection, 1 hour before ischemia and 3 hrs (hrs (hours)) after ischemia.
Experimental Results: Significant Improves spatial memory and memory abilities. The effect was Dramatically different from that of the sham operation group and the vehicle group.

Absorption, Distribution and Excretion
Oral pentoxifylline (PTX) is almost completely absorbed but has low bioavailability of 20-30% due to extensive first-pass metabolism; three of the seven known metabolites, M1, M4, and M5 are present in plasma and appear soon after dosing. Single oral doses of 100, 200, and 400 mg of pentoxifylline in healthy males produced a mean tmax of 0.29-0.41 h, a mean Cmax of 272-1607 ng/mL, and a mean AUC0-∞ of 193-1229 ng\*h/mL; corresponding ranges for metabolites 1, 4, and 5 were 0.72-1.15, 114-2753, and 189-7057. Single administration of a 400 mg extended-release tablet resulted in a heightened tmax of 2.08 ± 1.16 h, lowered Cmax of 55.33 ± 22.04 ng/mL, and a comparable AUC0-t of 516 ± 165 ng\*h/mL; all these parameters were increased in cirrhotic patients. Smoking was associated with a decrease in the Cmax and AUCsteady-state of metabolite M1 but did not dramatically affect the pharmacokinetic parameters of pentoxifylline or other measured metabolites. Renal impairment increases the mean Cmax, AUC, and ratio to parent compound AUC of metabolites M4 and M5, but has no significant effect on PTX or M1 pharmacokinetics. Finally, similar to cirrhotic patients, the Cmax and tmax of PTX and its metabolites are increased in patients with varying degrees of chronic heart failure. Overall, metabolites M1 and M5 exhibit plasma concentrations roughly five and eight times greater than PTX, respectively. PTX and M1 pharmacokinetics are approximately dose-dependent, while those of M5 are not. Food intake before PTX ingestion delays time to peak plasma concentrations but not overall absorption. Extended-release forms of PTX extend the tmax to between two and four hours but also serves to ameliorate peaks and troughs in plasma concentration over time.
Pentoxifylline is eliminated almost entirely in the urine and predominantly as M5, which accounts for between 57 and 65 percent of the administered dose. Smaller amounts of M4 are recovered, while M1 and the parent compound account for less than 1% of the recovered dose. The fecal route accounts for less than 4% of the administered dose.
Pentoxifylline has a volume of distribution of 4.15 ± 0.85 following a single intravenous 100 mg dose in healthy subjects.
Pentoxifylline given as a single 100 mg intravenous infusion has a clearance of 3.62 ± 0.75 L/h/kg in healthy subjects, which decreased to 1.44 ± 0.46 L/h/kg in cirrhotic patients. In another study, the apparent clearance of either 300 or 600 mg of pentoxifylline given intravenously (median and range) was 4.2 (2.8-6.3) and 4.1 (2.3-4.6) L/min, respectively. It is important to note that, due to the reversible extra-hepatic metabolism of the parent compound and metabolite 1, the true clearance of pentoxifylline may be even higher than the measured values.

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Metabolism / Metabolites
Pentoxifylline (PTX) metabolism is incompletely understood. There are seven known metabolites (M1 through M7), although only M1, M4, and M5 are detected in plasma at appreciable levels, following the general pattern M5 > M1 > PTX > M4. As PTX apparent clearance is higher than hepatic blood flow and the AUC ratio of M1 to PTX is not appreciably different in cirrhotic patients, it is clear that erythrocytes are the main site of PTX-M1 interconversion. However, the reaction likely occurs in the liver as well. PTX is reduced in an NADPH-dependent manner by unknown an unidentified carbonyl reductase to form either [lisofylline] (the (R)-M1 enantiomer) or (S)-M1; the reaction is stereoselective, producing (S)-M1 exclusively in liver cytosol, 85% (S)-M1 in liver microsomes, and a ratio of 0.010-0.025 R:S-M1 after IV or oral dosing in humans. Although both (R)- and (S)-M1 can be oxidized back into PTX, (R)-M1 can also give rise to M2 and M3 in liver microsomes. _In vitro_ studies suggest that CYP1A2 is at least partly responsible for the conversion of [lisofylline] ((R)-M1) back into PTX. Unlike the reversible oxidation/reduction of PTX and its M1 metabolites, M4 and M5 are formed via irreversible oxidation of PTX in the liver. Studies in mice recapitulating the PTX-ciprofloxacin drug reaction suggest that CYP1A2 is responsible for the formation of M6 from PTX and of M7 from M1, both through de-methylation at position 7. In general, metabolites M2, M3, and M6 are formed at very low levels in mammals.
Pentoxifylline is a known human metabolite of lisofylline.

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Biological Half-Life
Overall, pentoxifylline has an elimination half-life of between 0.39 and 0.84 hours, while its primary metabolites have elimination half-lives of between 0.96 and 1.61 hours.

Hepatotoxicity
Chronic therapy with pentoxifylline has not been associated with elevations in serum enzyme levels, although the rigor with which liver test abnormalities were sought in patients taking the drug was not always clear. Despite its use for more than 3 decades, pentoxifylline has been linked to only rare and not completely convincing cases of clinically apparent liver injury. Nevertheless, adverse effects of hepatitis, jaundice, cholestasis and increased liver enzymes are listed in product labels for pentoxifylline. In reported cases, the time to onset was 3 to 4 weeks and the pattern of liver enzyme elevations was distinctly cholestatic (Case 1). Autoimmune and immunoallergic features were not present. The injury was self-limited and there have been no reports of acute liver failure, chronic hepatitis or vanishing bile duct syndrome associated with pentoxifylline therapy.
In addition, pentoxifylline has been evaluated as the therapy of several liver diseases including acute alcoholic hepatitis and cirrhosis, nonalcoholic fatty liver disease and autoimmune liver conditions with varying results. In several small controlled trials in severe acute alcoholic hepatitis, pentoxifylline therapy was associated with a significant decrease in short term mortality and in the frequency of the hepatorenal syndrome. However, in large well controlled trials in alcoholic fatty liver, pentoxifylline with or without corticosteroids was found to have no effect on either short- or long-term mortality and minimal or no effect on rates of renal failure. Pentoxifylline has also been reported to improve serum aminotransferase levels and hepatic histology in adult patients with nonalcoholic steatohepatitis (NASH), but these findings have yet to be tested in larger randomized controlled trials. All studies, however, found pentoxifylline well tolerated in patients with liver disease and without evidence of hepatotoxicity.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited data indicate that pentoxifylline is poorly excreted into breastmilk. It would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Pentoxifylline is approximately 45% bound to erythrocyte membranes.

[1]. Pentoxifylline and its applications in dermatology. Indian Dermatol Online J. 2014 Oct-Dec; 5(4): 510–516.

[2]. Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs. 1987 Jul;34(1):50-97.

[3]. Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells. Int J Oncol. 2018 Apr;52(4):1246-1254.

[4]. Effect of Pentoxifylline on Ischemia- induced Brain Damage and Spatial Memory Impairment in Rat. Iran J Basic Med Sci. 2012 Sep-Oct; 15(5): 1083-1090.

Pharmacodynamics
Pentoxifylline, a synthetic dimethylxanthine derivative structurally related to [theophylline] and [caffeine], exhibits hemorheological, anti-oxidative, and anti-inflammatory properties and is traditionally indicated in the treatment of peripheral arterial disease (PAD). In PAD patients with concurrent cerebrovascular and coronary artery diseases, pentoxifylline treatment has occasionally been associated with angina, arrhythmia, and hypotension. Concurrent use with [warfarin] should be associated with more frequent monitoring of prothrombin times. Also, patients with risk factors complicated by hemorrhages, such as retinal bleeding, peptic ulceration, and recent surgery, should be monitored periodically for bleeding signs.

C13H18N4O3

278.30702

278.137

6493-05-6

Pentoxifylline-d6;1185878-98-1;Pentoxifylline-d5;1185995-18-9

4740

White to off-white solid powder

1.3±0.1 g/cm3

531.3±56.0 °C at 760 mmHg

98-100°C

275.1±31.8 °C

0.0±1.4 mmHg at 25°C

1.621

0.32

0

4

5

20

426

0

BYPFEZZEUUWMEJ-UHFFFAOYSA-N

InChI=1S/C13H18N4O3/c1-9(18)6-4-5-7-17-12(19)10-11(14-8-15(10)2)16(3)13(17)20/h8H,4-7H2,1-3H3

1,2,3,6-Tetrahydro-3,7-dimethyl-1-(5-oxohexyl)-2,6-purindion

Dimethyloxohexylxanthine; EHT-0202, EHT0202, EHT 0202; BL 191, BL191, BL-191; Oxpentifylline, Pentoxifilina, Theobromine, Trental, Vazofirin, Etazolate

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)

H2O : ~93.3 mg/mL (~335.24 mM)
DMSO : ≥ 2.8 mg/mL (~10.06 mM)

Solubility in Formulation 1: 110 mg/mL (395.24 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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