Dinemorphan N-demethylation by mouse liver microsomes

Area of Science:

• Pharmacology
• Drug Metabolism
• Biochemistry

Background:

• Dinemorphan is an antitussive agent.
• Understanding drug metabolism is crucial for pharmacokinetics and drug interactions.

Purpose of the Study:

• To investigate the in vitro N-demethylation of dinemorphan.
• To characterize the kinetic properties and identify the enzyme responsible for dinemorphan metabolism.

Main Methods:

• In vitro incubation of dinemorphan with mouse liver microsomes.
• Kinetic analysis to determine Michaelis-Menten constants (Km) and maximal velocities (Vmax).
• Inhibition studies using carbon monoxide (CO), SKF-525A, and metyrapone.

Main Results:

• Dinemorphan N-demethylation exhibited biphasic kinetics, indicating at least two distinct enzymatic pathways.
• The metabolism was significantly inhibited by CO, SKF-525A, and metyrapone, suggesting cytochrome P-450 involvement.
• A phenobarbital-inducible form of cytochrome P-450 was identified as the specific catalyst.

Conclusions:

• Dinemorphan undergoes N-demethylation through a complex, biphasic kinetic process in mouse liver microsomes.
• Cytochrome P-450 enzymes, particularly a phenobarbital-inducible isoform, are responsible for dinemorphan metabolism.
• The findings provide insights into the metabolic pathways and potential drug interactions of dinemorphan.