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Pharmacology: Pharmacodynamics: Bleomycin belongs to cytostatic antibiotics: It is a mixture of structurally related, alkaline, water-soluble, glycopeptide antibiotics with a cytostatic effect. The activity of Bleomycin is based on intercalation with single-helix and double-helix DNA, resulting in single-helix and double-helix breaks, which inhibit cell division, growth and DNA synthesis.
To a lesser extent bleomycin influences the RNA and protein synthesis. The main factor in the tissue selectivity of Bleomycin is the difference in intracellular inactivation. Cells at the G2 and M stage of the cell cycle are the most sensitive. Squamous cells, with their small percentage of bleomycin hydrolase, have an increased sensitivity to Bleomycin. In sensitive tissues, both normal and neoplastic, chromosomal disorders such as fragmentation, chromatid breaks and translocations will often be produced.
Contrary to the most other cytostatics, bleomycin is hardly toxic to the bone marrow, causes no immunosuppression and is not neurotoxic or cardiotoxic. In patients suffering from testicular tumours who were treated with bleomycin, a disorder of the coronary arteries has been described.
The above toxicity profile makes bleomycin suitable foradministration in combination with other cytostatics.
Pharmacokinetics: Bleomycin is administered parenterally.
After intravenous administration of 15 U/m2 body surface via a bolus injection, maximum plasma concentrations are obtained of 1 to 10 x 10-3 U per mL. After intramuscular injection of 15 U bleomycin, maximum plasma concentrations of 1 x 10-3 U per mL are obtained after 30 minutes.
Continuous infusion of 30 U bleomycin daily for 4 to 5 days results in an average steady state plasma concentration of 100 to 300 x 10-6 U per mL.
Distribution: Bleomycin is rapidly distributed over the body tissues, with the highest concentration in the skin, the lungs, the peritoneum and the lymph. Low concentrations are only found on the bone marrow. Bleomycin has not been detected in the cerebrospinal fluid after intravenous injection.
The distribution volume in humans (about 22 L) is larger than the volume of extracellular water.
In the plasma, bleomycin is bound to plasma proteins only to a small extent.
Biotransformation: The biotransformation is not entirely known.
Inactivation of bleomycin takes place by enzymatic decomposition by bleomycin hydrolase, particularly in plasma, liver and other organs, and to a lesser extent in skin and lungs.
Elimination: After intravenous administration of a bolus dose, bleomycin is rapidly cleared and two phases of elimination are apparent. A short initial phase (t½α: 10-25 min.) is followed by a longer terminal phase (t½β: 2-6 h). After continuous intravenous infusion, the elimination half life can increase to about 9 hours.
Approximately 2/3 of the quantity of bleomycin administered is excreted unchanged in the urine, probably by glomerular filtration. The greater part of the dose is excreted within 8-12 hours.
This indicates that the excretion rate is largely influenced by the renal function. Plasma concentrations are sharply increased if usual doses are given to patients with renal function disorders. Observations show that it is difficult to eliminate Bleomycin by dialysis.
Toxicology: Preclinical safety data: Animal tests have shown that bleomycin is teratogenic and carcinogenic (see Use in Pregnancy and Lactation under Precautions).
