Kinetics of intravenous melphalan.

Area of Science:

• Pharmacology
• Oncology
• Drug Metabolism

Background:

• Melphalan is a key chemotherapeutic agent used in cancer treatment.
• Understanding its disposition and elimination is critical for effective therapeutic use.
• Previous studies have not fully elucidated the primary elimination pathway of melphalan.

Purpose of the Study:

• To investigate the pharmacokinetic profile of melphalan following intravenous administration.
• To determine the primary mechanism responsible for melphalan's elimination from the body.
• To quantify melphalan excretion and identify its metabolites in cancer patients.

Main Methods:

• Intravenous administration of melphalan to 9 cancer patients.
• Quantification of drug concentrations in plasma and urine using high-pressure liquid chromatography and radiolabeled 14C-melphalan.
• Analysis of plasma and urine samples to identify parent compound, metabolites, and protein-bound activity.

Main Results:

• Composite plasma half-life (t1/2alpha) was 7.7 ± 3.3 min and (t1/2beta) was 108 ± 20.8 min in 8 patients.
• Mean 24-hour urinary excretion of melphalan was 13.0 ± 5.4% of the administered dose.
• In 2 patients, parent compound, metabolites, and protein-bound activity accounted for 80-100% of 14C counts, suggesting minimal enzymatic metabolism.

Conclusions:

• Spontaneous degradation, rather than enzymatic metabolism, is the major determinant of melphalan's in vivo half-life.
• Rapid disappearance from plasma supports the hypothesis of non-enzymatic degradation.
• These findings have significant implications for melphalan dosing and therapeutic strategies in oncology.