Metabolic Fate of Esmolol.

Miyamoto, Yukio; Murasaki, Yuko; Okamura, Miyako; Kumagai, Masamichi; Ohkura, Takako; Kawai, Yoichiro; Tamura, Takashi; Takariki, Y.; Tomisawa, Hiroki

doi:10.2133/dmpk.16.415

Cited by 2 publications

(2 citation statements)

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“…The hepatic clearance of esmolol, calculated by its intrinsic clearance (841 mL/min/kg bodyweight) and its plasma protein binding of 40%, was equal to hepatic blood flow, indicating rapid metabolism in human liver. 20) However, the hepatic clearance of esmolol was 7.2% of systemic clearance (285 mL/min/kg bodyweight), 1,4) while its blood clearance was only 0.5% of systemic clearance. The high systemic clearance of esmolol, compared with the average normal adult cardiac output of 80.0 mL/min/kg bodyweight, can be accounted for by first-pass metabolism.…”

Section: Discussionmentioning

confidence: 98%

“…The blood volume (V B ) used was 74.3 mL/kg bodyweight. 12) The hepatic blood flow rate (Q H = 20.7 mL/min/kg bodyweight) 19) and free fraction in blood for esmolol ( f u = 0.61) 20) were used in the calculation. The intrinsic hepatic clearance (CL int, H ) was estimated from Michaelis-Menten kinetic parameters and protein content in human liver microsomes according to the following equation: CL int, H = (V max /K m ) × (protein content).…”

Section: Hydrolysis Of Esmolol In Human Liver Fractions and Inhibitio...mentioning

confidence: 99%

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

Imai

Isozaki

Ohura

2022

Biological & Pharmaceutical Bulletin

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Esmolol is indicated for the acute and temporary control of ventricular rate due to its rapid onset of action and elimination at a rate greater than cardiac output. This rapid elimination is achieved by the hydrolysis of esmolol to esmolol acid. It has previously been reported that esmolol is hydrolyzed in the cytosol of red blood cells (RBCs). In order to elucidate the metabolic tissues and enzymes involved in the rapid elimination of esmolol, a hydrolysis study was performed using different fractions of human blood and liver. Esmolol was slightly hydrolyzed by washed RBCs and plasma proteins while it was extensively hydrolyzed in plasma containing white blood cells and platelets. The negligible hydrolysis of esmolol in RBCs is supported by its poor hydrolysis by esterase D, the sole cytosolic esterase in RBCs. In human liver microsomes, esmolol was rapidly hydrolyzed according to Michaelis-Menten kinetics, and its hepatic clearance, calculated by the wellstirred model, was limited by hepatic blood flow. An inhibition study and a hydrolysis study using individual recombinant esterases showed that human carboxylesterase 1 isozyme (hCE1) is the main metabolic enzyme of esmolol in both white blood cells and human liver. These studies also showed that acyl protein thioesterase 1 (APT1) is involved in the cytosolic hydrolysis of esmolol in the liver. The hydrolysis of esmolol by hCE1 and APT1 also results in its pulmonary metabolism, which might be a reason for its high total clearance (170-285 mL/min/kg bodyweight), 3.5-fold greater than cardiac output (80.0 mL/min/kg bodyweight).

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Section: Discussionmentioning

confidence: 98%

Section: Hydrolysis Of Esmolol In Human Liver Fractions and Inhibitio...mentioning

confidence: 99%