Hydrolysis and protein binding of melphalan

Area of Science:

• Pharmacokinetics
• Drug Stability
• Chemical Kinetics

Background:

• Melphalan is a chemotherapy drug with limited stability in aqueous solutions.
• Understanding melphalan's degradation pathways is crucial for optimizing its clinical use and formulation.

Purpose of the Study:

• To investigate the hydrolysis kinetics of melphalan in water.
• To determine the effect of bovine serum albumin (BSA) on melphalan stability.
• To compare melphalan stability in BSA solutions to that in human plasma.

Main Methods:

• Melphalan hydrolysis was studied in water at 37°C.
• The influence of varying concentrations of bovine serum albumin on hydrolysis rates was assessed.
• Melphalan stability in human plasma was evaluated using equilibrium dialysis, methanol extraction, and HPLC analysis.

Main Results:

• Melphalan (30 µg/ml) completely hydrolyzed in water within 8 hours at 37°C.
• Hydrolysis rates decreased at lower temperatures.
• Bovine serum albumin significantly retarded melphalan hydrolysis in a concentration-dependent manner.
• A concentration of 8 g/100 ml BSA in water at 37°C yielded melphalan recovery rates comparable to human plasma.
• In vitro alkylation of melphalan in human plasma was 30% after 8 hours at 37°C.

Conclusions:

• Melphalan exhibits rapid hydrolysis in aqueous environments.
• Bovine serum albumin effectively stabilizes melphalan, with concentrations mimicking human plasma achieving significant protection.
• These findings have implications for the formulation and administration of melphalan-based therapies.