Pentoxifylline

Absorption

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.

Toxicity

Overdoses of pentoxifylline have been reported with symptoms including agitation, fever, flushing, hypotension, convulsions, somnolence, and loss of consciousness beginning 4-5 hours following ingestion and lasting up to 12 hours. Symptomatic treatment is recommended, specifically pertaining to maintaining proper respiration, blood pressure, and controlling convulsions. Activated charcoal may prove useful in absorbing excess pentoxifylline in overdose cases. Patients have recovered from overdose even at doses as high as 80 mg/kg.

The Uses of Pentoxifylline

Pentoxifylline is a methylxanthine phospho-diesterase inhibitor with favorable antiinflammatory effects and immunoregulatory properties.
A metabolite of Pentifylline. Methylxanthine derivative that improves blood flow by decreasing blood viscosity. Phosphodiesterase inhibitor. Inhibits the synthesis of tumor necrosis factor a (TNF-a).

Background

Pentoxifylline (PTX) is a synthetic dimethylxanthine derivative that modulates the rheological properties of blood and also has both anti-oxidant and anti-inflammatory properties. Although originally developed to treat intermittent claudication, a form of exertion-induced leg pain common in patients with peripheral arterial disease, PTX has been investigated for its possible use in diverse conditions, including osteoradionecrosis, diabetic kidney disease, and generally any condition associated with fibrosis. More recently, PTX has been suggested as a possible treatment for COVID-19-induced pulmonary complications due to its ability to regulate the production of inflammatory cytokines.
Pentoxifylline has been marketed in Europe since 1972; PTX extended-release tablets sold under the trade name TRENTAL by US Pharm Holdings were first approved by the FDA on Aug 30, 1984, but have since been discontinued. A branded product, PENTOXIL, marketed by Upsher-Smith Laboratories, and generic forms marketed by Valeant Pharmaceuticals and APOTEX have been available since the late 1990s.

Indications

Pentoxifylline is indicated for the treatment of intermittent claudication in patients with chronic occlusive arterial disease. Pentoxifylline may improve limb function and reduce symptoms but cannot replace other therapies such as surgical bypass or removal of vascular obstructions.

What are the applications of Application

Pentoxifylline is a non-selective phosphodiesterase inhibitor. Inhibits endotoxin-induced synthesis of TNF-α

Pharmacokinetics

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.

Metabolism

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.