Esterases Involved in the Rapid Bioconversion of Esmolol after Intravenous Injection in Humans

Area of Science:

• Pharmacology
• Drug Metabolism
• Biochemistry

Background:

• Esmolol is used for rapid ventricular rate control.
• Its rapid elimination exceeds cardiac output.
• Hydrolysis is the primary elimination pathway.

Purpose of the Study:

• To identify tissues and enzymes responsible for esmolol hydrolysis.
• To elucidate the metabolic pathways of esmolol elimination.

Main Methods:

• Hydrolysis studies using human blood fractions (RBCs, plasma, WBCs, platelets) and liver microsomes.
• Enzyme inhibition studies with recombinant esterases.
• Kinetic analysis using Michaelis-Menten models.

Main Results:

• Esmolol hydrolysis is extensive in plasma with WBCs and platelets, minimal in RBCs.
• Human carboxylesterase 1 (hCE1) is the primary enzyme in WBCs and liver.
• Acyl protein thioesterase 1 (APT1) contributes to liver cytosolic hydrolysis.
• Hepatic clearance is limited by hepatic blood flow.

Conclusions:

• hCE1 and APT1 are key enzymes in esmolol metabolism.
• Pulmonary metabolism contributes to high esmolol clearance.
• These findings explain esmolol's rapid elimination profile.