Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cytotoxic antibiotics and related substances ATC code: L01DC01
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 in turn leads to inhibition of cell division, growth and DNA synthesis. Bleomycin can also influence RNA (ribonucleic acid) and protein biosynthesis to a lesser extent.
The tissue selectivity of bleomycin is primarily due to differences in intracellular inactivation.
With their low content of bleomycin hydrolase, squamous epithelial cells are highly sensitive to bleomycin. Chromosome aberrations, such as fragmentation, chromatin strand breaks, and translocations occur in sensitive tissues, both healthy and neoplastic.
Bleomycin has pyrogenic properties.
Bleomycin causes little or no bone marrow toxicity and no immunosuppression.
Bleomycin can be used alone or in combination with radiotherapy or other cytostatic agents.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Bleomycin is absorbed to a very limited extent after oral administration. After intravenous bolus injection of 15 units (USP)/m² BSA, maximum plasma levels of 1- 10 µg/mL are reached after around 10 minutes. After IM injection of 15 units, maximum plasma levels of around 1 µg /mL are reached after 30 minutes. Continuous infusion of 30 units (USP) bleomycin over 4- 5 days leads to a mean steady- state concentration in plasma of 100-300 ng/mL.
After intrapleural or intraperitoneal use, bleomycin is absorbed systemically. After intrapleural administration, approximately 45% of the dose is absorbed into the circulation.


Distribution
Bleomycin is rapidly distributed in the tissues and the highest concentrations are reached in the skin, lungs, peritoneum and lymphatic system. Low concentrations are found in the bone marrow. Bleomycin is undetectable in CSF after intravenous injection. Bleomycin crosses the placenta. The apparent volume of distribution (Vd)ß is assumed to be about 0.27±0.09 L/kg.
The plasma protein binding of bleomycin is minimal.


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


Elimination
The elimination half-life (T ½ ß) is around 3 hours. After continuous IV infusion, the elimination half-life may increase to 9 hours. The systemic plasma clearance (ClS) is around 1.1 mL/min x kg bodyweight. Approximately 2/3 of the administered dose is excreted unchanged in the urine, probably by glomerular filtration.
After IV or IM injection, about 50% of the active substance is recovered in the urine. .In renal impairment , the half-life is considerably prolonged so that dose reductions are required. When creatinine clearance is <35 mL/min, renal excretion decreases to less than 20% and plasma levels may be increased. Previous observations show that bleomycin is barely if at all eliminated by dialysis.