Adrim Mechanism of Action

Pharmacology: Mechanism of Action: Doxorubicin binds directly to DNA via intercalation between base pairs on the DNA helix. Doxorubicin also inhibits DNA repair by inhibiting topoisomerase II. These actions result in the blockade of DNA and RNA synthesis and fragmentation of DNA. Doxorubicin is also a powerful iron-chelator. The iron-doxorubicin complex can bind DNA and cell membranes producing free radicals that immediately cleave DNA and cell membranes. Although maximally cytotoxic in S phase, doxorubicin is not cell cycle-specific.
Pharmacokinetics: Pharmacokinetic studies conducted in patients with various types of tumors have shown that doxorubicin follows multiphasic disposition after intravenous injection. The distribution half-life is approximately 5 minutes, while the terminal half-life is 20 to 48 hours.
Distribution: Steady-state distribution volume ranges from 809 to 1214 L/m². Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 75%.
Doxorubicin does not cross the blood brain barrier.
Metabolism: It undergoes rapid metabolism in the liver to metabolites including the active metabolite doxorubicinol (adriamycinol).
Excretion: Plasma clearance is in the range 324 to 809 mL/min/m² and is predominately by metabolism and biliary excretion. Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% of the drug and its metabolites appear in the urine during the same time period. In urine, <3% of the dose was recovered as doxorubicinol over 7 days. Systemic clearance of doxorubicin is significantly reduced in obese women with ideal body weight greater than 130%. There was a significant reduction in clearance without any change in volume of distribution in obese patients when compared with normal patients with less than 115% ideal body weight.
Pediatric patients: Clearance in children older than 2 years was increased compared with adults.
Patient Gender: Clearance appears to be higher in men than women; however, the half-life was longer in men compared with women.
Patients with hepatic impairment: The clearance of doxorubicin and doxorubicinol was reduced in patients with elevation in serum bilirubin.