Bleomycin

Bleomycin is a mixture of basic, water-soluble glycopeptide-antibiotics with cytotoxic activity. Bleomycin acts by interacting with both single and double-stranded DNA (deoxyribonucleic acid) leading to both single and double-strand scission, which leads in turn to inhibition of cell division, inhibition of growth and inhibition of DNA synthesis. Bleomycin can also influence RNA (ribonucleic acid) and protein biosynthesis to a lesser extent.

The main factor in the tissue selectivity of bleomycin is differences in intracellular inactivation. Squamous cells, with their low bleomycin hydrolase content, are highly sensitive to bleomycin. Chromosome aberrations such as fragmentation, chromatid breaks, and translocations occur in sensitive tissues, both healthy and neoplastic.

Bleomycin can be pyrogenic. It causes little or no bone-marrow toxicity and no immunosuppression.

Bleomycin can be used alone, or in combination with radiotherapy or other cytotoxic agents.

Absorption

Bleomycin is absorbed to a very limited extent orally. Following intravenous bolus injection of 15 × 10³ IU/m² BSA, peak plasma concentrations of 1-10 IU are reached after approximately 10 minutes. Following i.m. injection of 15 × 10³ IU, maximum plasma levels of approximately 1 IU are reached after 30 minutes. Continuous infusion of 30 × 10³ IU of bleomycin over 4-5 days results in an average steady-state plasma concentration of 1-3 IU/mL.

Following intrapleural or intraperitoneal administration, bleomycin is systemically absorbed. Following intrapleural administration, approximately 45% of the dose is absorbed into the circulation.

Distribution

Bleomycin is rapidly distributed to the tissue, with the highest concentrations accumulating in the skin, lungs, peritoneum and lymph nodes. Low concentrations are found in the bone marrow. Bleomycin is not detectable in the cerebrospinal fluid following intravenous injection. Bleomycin crosses the placental barrier. The apparent volume of distribution (V_d)_β is assumed to be approx. 0.27 +/- 0.09 L/kg. Bleomycin only binds to plasma proteins to a limited extent.

Biotransformation

The inactivation is performed by hydrolases, which have been detected in the plasma, liver, spleen, intestine and bone marrow. In contrast, the enzymatic activity of the hydrolases is low in the skin and lungs.

Elimination

The elimination half-life (T_½β) is approx. 3 hours after intravenous administration of a bolus injection. Two phases of elimination occur, a brief initial phase (t_½α; 24 min.) followed by a longer terminal phase (t_½β; 2–4 hours). After continuous i.v. infusion, the elimination half-life may increase to 9 hours. The systemic plasma clearance (Cls) is approximately 1.1 mL/min/kg bw. Approximately ⅔ of the dose administered is excreted unchanged in the urine, probably by glomerular filtration.

After an i.v. or i.m. injection, approximately 50% of the active substance is recovered in the urine. The half-life is considerably prolonged in patients with impaired renal function, to the extent that dose reductions are required. With a creatinine clearance of 35 mL/min, the renal excretion decreases to below 20% with the risk of increased plasma levels. Previous observations indicate that bleomycin is difficult to dialyze.

Animal experiments have demonstrated teratogenic, mutagenic and carcinogenic properties for bleomycin. Mutagenic effects in humans are expected at clinically relevant exposure levels.

With respect to reproduction toxicity various effects were observed in mice and rats. In rabbits no teratogenicity was observed. In the mouse the female reproductive cells were more sensitive to the cytotoxic and mutagenic effects of bleomycin than the male cells.

Chromosomal abnormalities were observed in human bone marrow cells. The meaning of this for the embryonic/foetal development in humans is unknown.