Acridinyl Anisidide

Amsacrine

Pharmacodynamic Properties

Amsacrine is a synthetic acridine-derivate. Though the mode of action is not fully understood, it is accepted that amsacrine binds to DNA by intercalation and external electrostatic binding. The synthesis of DNA is inhibited. DNA-fragmentation and chromosomal changes occur. RNA-synthesis is not changed.

Clinically no cross resistance has been found with antracycline antibiotics such as doxorubicine and daunorubicine.

Amsacrine gave in refractory patients a remission of short duration in 20-30 % of patients.

Pharmacokinetic Properties

Distribution

Amsacrine is extensively bound to tissue, probably especially to membrane structures. Also there exists a strong binding to plasma proteins which is concentration dependant. In animal experiments amsacrine penetrates the CNS system. The partition volume of amsacrine is about 1,5-2 l/kg bodyweight.

Metabolism

Amsacrine is metabolised mainly in the liver. Plasma-elimination curve shows firstly a fast decline (distribution phase) followed by an elimination phase with a halflife of 6-9 hours. The halflife of the slow phase is considerably longer in patients with hepatic insufficiency (till more than 17 hours). Mild to moderate kidney insufficiency has hardly an effect on pharmacokinetics of amsacrine.

Excretion

Renal clearance of unchaged amsacrine is about 4% of total body clearance which is 200-500 ml/min. Inactive metabolites are excreted with the bile.

Preclinical Safety Data

Amsacrine caused embryotoxicity and teratogenicity in rats and mice. In view of its mechanism of action, amsacrine should be considered a potential carcinogen and mutagen in man.

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