Pharmacology: Although the precise mechanism of action of bleomycin is not fully known, it is thought that the primary action is to produce single and double-strand breaks in DNA, leading to inhibition of cell division and growth, and inhibition of DNA synthesis in the cells.
Bleomycin is probably most effective against cells in the M and G2 (premitotic) phase of the cell cycle. Bleomycin has not been shown to have an immunosuppressive effect in vitro and shows no significant inhibition of immune response in patients treated with the drug.
Bleomycin-inactivating enzyme has been detected in both normal and malignant cells and is particularly prominent in liver. The enzyme is not found in lung or skin, two normal tissues sensitive to bleomycin action.
Pharmacokinetics: Absorption: Bleomycin is well absorbed in animals upon parenteral administration. Intramuscular injection of 15 units in man resulted in a maximum serum concentration of 1 milliunit/mL thirty minutes after administration. Intravenous injection of 15 units in man resulted in a maximum serum concentration of 3.3 milliunits/mL.
Distribution: In mice, bleomycin diffusing from the blood produces high concentrations in the skin, lungs, kidneys, peritoneum, lymphatic system and susceptible tumour tissue if present. Bleomycin crosses the placenta, but does not cross the blood brain barrier. Equilibrium dialysis and gel permeation experiments suggest that less than 1.0% of the drug is protein-bound after incubation with normal human serum in vitro.
Metabolism: The majority of a bleomycin dose is not readily metabolised. The highest rate of metabolism occurs in the liver and gastrointestinal tract. A lower rate of metabolism also occurs in skin, lungs, kidneys, muscle and serum. The products of bleomycin metabolism are not known.
Elimination: Bleomycin is primarily excreted in the urine. After intravenous injection an average of 40% of the administered dose is recovered unchanged in the urine within 24 hours. After IM injection 20% is recovered in the urine after 6 hours. The plasma half-lives have varied from 15-60 minutes in patients with normal renal function following intravenous administration. The serum half-life is prolonged in patients with renal dysfunction. In one patient with severe renal dysfunction the biological half-life was 21 hours when the creatinine clearance was 10.7 mL/min, and 13 hours when the creatinine clearance was 15.2mL/min. There were undetectable serum levels of bleomycin 72 hours after the intravenous dose.