Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

Abstract

Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed.

Enantioresolution and Binding Affinity Studies on Human Serum Albumin: Recent Applications and Trends

“…Separation of enantiomers is undoubtedly a matter of crucial importance in diverse research areas [44], allowing to achieve different goals, such as preparative enantioresolution of chiral drugs and other analytes [177,178], monitoring enantiomeric reactions [167,179], evaluation of enantiomeric purity in quality control [180,181], food analysis [182,183], stereochemistry determination of natural compounds [184,185], pharmacokinetic [25] and environmental studies [186,187], among other applications.…”

“…Considering the interaction with chiral molecules, plasma proteins, as well as other biomolecules comprising intrinsic chirality, such as enzymes, transporters or receptors, generally have a higher affinity for one of the enantiomers (enantioselectivity) [22]. As a consequence, the enantiomers may exhibit different pharmacodynamic, pharmacokinetic and/or toxicological properties [23][24][25][26]. Typically, when one enantiomer is responsible for the biological activity of interest, the other could be inactive, possess lower activity, be an antagonist of the active enantiomer or have a different activity that could be desirable or undesirable [27,28].…”

Cytochrome P450 Enzymes and Drug Metabolism in Humans

“…The majority of drugs lipophilic centers are converted to hydrophilic centers during drug biotransformation, which can increase their water solubility, to allow elimination in urine or bile [ 3 ]. This is an important progress for drug metabolism, because the lipophilic nature of drugs can keep them staying for longer in the body, which may in turn lead to toxicity [ 4 , 5 ]. Drug metabolism can be divided into phase I and phase II reactions [ 6 ].…”

Tackling Stereochemistry in Drug Molecules with Vibrational Optical Activity

“…Nonetheless, this example best illustrates the importance of chirality in pharmacy and the need for reliable tools for full stereochemical elucidation and subsequent characterization of the pharmacological/toxicological profile of each stereoisomer individually before any clinical trial. The interaction of chiral drugs with the human organism is multifactorial and marked differences between stereoisomers may be observed both in pharmacokinetics (absorption, bioavailability, distribution, metabolism, excretion) [7,8] and pharmacodynamics (receptor binding, chemical interaction, post receptor effects) parameters [4,9,10]. Apart from cases where one enantiomer is active and the other one is toxic, as in thalidomide, a number of other chiral drugs have also been demonstrated to possess distinct biological activity for its enantiomers.…”

“…The interaction of chiral drugs with the human organism is multifactorial and marked differences between stereoisomers may be observed both in pharmacokinetics (absorption, bioavailability, distribution, metabolism, excretion) [ 7 , 8 ] and pharmacodynamics (receptor binding, chemical interaction, post receptor effects) parameters [ 4 , 9 , 10 ]. Apart from cases where one enantiomer is active and the other one is toxic, as in thalidomide, a number of other chiral drugs have also been demonstrated to possess distinct biological activity for its enantiomers.…”