Applicability of the Rayleigh equation for enantioselective metabolism of chiral xenobiotics by microsomes, hepatocytes and in-vivo retention in rabbit tissues

Abstract

In this study we propose a new approach for analyzing the enantioselective biodegradation of some antidepressant drugs mediated by human and rat liver microsomes by using the Rayleigh equation to describe the enantiomeric enrichment−conversion dependencies. Analysis of reported degradation data of additional six pesticides, an alpha blocker and a flame retardant by microsomes or hepatocytes in vitro reaffirmed the universality of the approach. In all the in vitro studied cases that involved enantioselective degradation, a Rayleigh dependence of the enantiomeric enrichment was observed. Published data regarding in vivo retention of myclobutanil in liver, kidney, muscle and brain tissues of rabbits following injection of the racemate were remodeled showing prevalence of the Rayleigh law for the chiral enrichment of the fungicide in the various tissues. This approach will revolutionize data organization in metabolic pathway research of target xenobiotics by either liver microsomes, hepatocytes or their organ-specific in vivo retention. The fact that the enantiomeric enrichment as a function of the conversion can be described by a single quantifier, will pave the road for the use of structure activity predictors of the enantiomeric enrichment and for mechanistic discrimination based on parametric dependence of the quantifier.

Enantiomer-specific stable carbon isotope analysis (ESIA) to evaluate degradation of the chiral fungicide Metalaxyl in soils

“…This concept is modeled in lab experiments by the Rayleigh equation that relates isotopic ratios to the extent of biodegradation by isotopic fractionation factors ε [15]. Analogously, the Rayleigh concept can also be applied to model enantioselective biodegradation [16]. Magnitude of ε C depends on many factors, including the number of carbon atom in the molecule, the type of bond broken (e.g., CeH or CeO), the effects of non-reacting positions and intramolecular competition [17].…”

High‐performance liquid chromatography quantification of enantiomers of a Dihydroxylated tetrahydrofuran natural product

“…Chirality is a critical attribute of biologically active organic compounds. For example, absolute stereochemistry is important for many enzymatic reactions, messenger‐receptor interactions, and metabolic processes, and is a critical factor to consider when studying xenobiotics such as drugs, agrochemicals, food additives, flavors, and fragrances . Numerous examples from studies on pheromones, chemical signals used by most organisms, attest to the fundamental and broad importance of chirality in nature .…”

“…For example, absolute stereochemistry is important for many enzymatic reactions, messenger-receptor interactions, and metabolic processes, and is a critical factor to consider when studying xenobiotics such as drugs, agrochemicals, food additives, flavors, and fragrances. [1][2][3] Numerous examples from studies on pheromones, chemical signals used by most organisms, 4 attest to the fundamental and broad importance of chirality in nature. 5 It is common that only one enantiomer is responsible for a pheromone's activity and that its antipode does not inhibit the response, as is the case with the spider Linyphia triangularis.…”

Novel N-Doped Carbon Dots/β-Cyclodextrin Nanocomposites for Enantioselective Recognition of Tryptophan Enantiomers

“…The enantiomeric forms of chiral drugs usually show different pharmacological/metabolic behaviors in biological systems, and the demand for single-enantiomer drugs has substantially increased throughout the world, so the enantioselective recognition of enantiomeric forms of chiral molecules has attracted huge attention in the field of analytical and pharmaceutical research [1,2,3,4]. Since the natural amino acids in human beings are predominantly l -isomers and the presence of d -isomers in life forms usually indicates negative symptoms, the discrimination of amino acid enantiomers is thus of great interest and increasing importance in chemical, biological and pharmaceutical sciences [5,6].…”