Hence, pentoxifylline promotes microcirculatory perfusion by improving the fluidity of the blood and by exerting antithrombotic effects.

Peripheral resistance may be reduced slightly if pentoxifylline is administered in high doses or by rapid infusion. Pentoxifylline exerts a mild inotropic effect on the heart.

5.2 Pharmacokinetic properties

 The half-life of absorption of Trental 400 is 4 – 6 hours. Pentoxifylline is extensively metabolised, mainly in the liver. Sixty percent of a single dose of Trental 400 is eliminated via the kidney over 24 hours.

After oral administration, absorption of pentoxifylline is rapid and almost complete.

After almost complete absorption, pentoxifylline undergoes a “first pass “metabolism. The absolute bioavailability of the parent compound is 19 ± 13%. The active main metabolite 1-(5-hydroxyhexyl)-3,7-dimethyl-xanthine(metabolite I) is measurable in twice the concentration in plasma of that of its parent substance, with which it is in reversible biochemical redox-equilibrium. For this reason pentoxifylline and metabolite I are to be regarded as an active unit, and the availability of active substance is therefore significantly greater.

The elimination half-life of pentoxifylline after oral or intravenous administration is approx. 1.6 hours.

Pentoxifylline is completely metabolized and more than 90% is eliminated via the renal route in the form of unconjugated water-soluble polar metabolites. Metabolite excretion is delayed in patients with severely impaired renal function.

In patients with impaired liver function the elimination half-life of pentoxifylline is prolonged and the absolute bioavailability is increased.

5.3 Preclinical safety data

 Acute toxicity

Acute toxicity studies have shown LD50 values in mice of 195 mg/kg body weight after intravenous and 1385 mg/kg body weight after oral administration, respectively, and in rats of 230 mg/kg body weight after intravenous and 1770mg/kg bodyweight after oral administration, respectively. This means that toxicity of pentoxifylline is low.

Chronic toxicity

Chronic toxicity studies showed no substance-related toxic organ damage following administration of pentoxifylline over 1 year to rats in daily does of up to 1000 mg/kg body weight and to dogs in daily doses of up to 100 mg/kg body weight . In one study, following doses of 320mg/kg body weight or higher given to dogs over one year, several animals showed lack of co-ordination, circulatory failure, bleedings, pulmonary oedema or giant cells in the testes.

Mutagenicity

Mutagenicity testing (Ames test, micronucleus test, UDS test) has revealed no evidence of a mutagenic effect.

Carcinogenicity

In mice given oral doses of pentoxyifylline up to 450mg/kg body weight daily over 18 months, no indications of any carcinogenic effects were revealed.

In female rats receiving oral doses of pentoxifylline up to 450mg/kg body weight daily over 18 months, an increased number of benign mammary fibroadenomas were observed. However, benign mammary fibroadenomas often occur spontaneously in older rats.
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