Evaluation of the metabolism of propranolol by linear ion trap technology in mouse, rat, dog, monkey, and human cryopreserved hepatocytes

Abstract

Propranolol is a widely used quality control and validation compound for liver microsome and hepatocyte metabolism studies. A multitude of literature reports describing the identification of propranolol metabolites exists today. However, no literature reports currently exist showing hepatocyte metabolism across the five species commonly used during pre-clinical drug discovery, namely mouse, rat, dog, monkey, and human. Herein, we present full metabolic profiles of propranolol in mouse, rat, dog, monkey and human hepatocytes. As expected, extensive phase I and phase II metabolism was observed across all five species and species-specific metabolites were detected in monkey and dog hepatocytes. Of particular interest was the detection of an N-hydroxylamine glucuronide metabolite in monkey and dog hepatocytes.

Human FMO2-based microbial whole-cell catalysts for drug metabolite synthesis

“…Based on mass selective detection, also N -dealkylation can be ruled out and nitrone formation seems unlikely. As described by Baughman et al for propranolol conversions with hepatocytes of various species [32], the isopropyl part can be oxidized and one could speculate that this reaction may have been catalyzed by FMO2. It remains to be clarified if the product mixture was a result of low metabolite stability in solution, rearrangement reactions or FMO2 selectivity towards propranolol.…”

Propranolol impairs liver regeneration after partial hepatectomy in C57Bl/6-mice by transient attenuation of hepatic lipid accumulation and increased apoptosis

“…The relatively high effective dose of oral propranolol in our experiments correlates with the high firstpass hepatic turnover of this drug in rodents compared to non-rodents [30,31]. Comparable doses of propranolol were used by Hong et al [12] to suppress PCNA expression and DNA synthesis in rat liver regeneration.…”

Determination of selected cardiovascular active compounds in environmental aquatic samples – Methods and results, a review of global publications from the last 10 years

“…fenofibrate, clofibrate, enalapril are active only after the metabolic activation of the parent compound by enzymes. On top of that partial degradation of pharmaceuticals and their metabolites during wastewater treatment processes transformation products may form or during the wastewater process drug conjugates can be hydrolyzed back to the free parent drug (Baughman et al, 2009). Similarly in river waters, we could expect the same situation, the hydrolysis of drug's conjugates by bacteria.…”

“…Recently, the in vitro models are promoted including not only whole cell systems (intact perfused liver, human hepatocytes cultures, hepatic and transfected cell lines), but also enzyme preparations (liver microsomes, cytosolic and S9 fractions). As an example of recently reported in vitro biotransformation studies we would like to present two publications: Baughman et al (2009) described interspecies differences of specific cytochrom's isoforms (from animal models to humans). The authors used the incubation of previously cryopreserved hepatocytes of 5 different species (including humans) to obtain propranolol's metabolites.…”