Pharmacokinetic properties enantiomers

It was apparent that the FDA recognized the ability of the pharmaceutical industry to develop chiral assays. With the advent of chiral stationary phases (CSPs) in the early 1980s [8, 9], the tools required to resolve enantiomers were entrenched, thus enabling the researcher the ability to quantify, characterize, and identify stereoisomers. Given these tools, the researcher can assess the pharmacology or toxicology and pharmacokinetic properties of enantiopure drugs for potential interconversion, absorption, distribution, and excretion of the individual enantiomers. 

At the cellular level, the various types of receptor, transporter, enzyme and ion charmel are all chiral in form. Thus although the enantiomers of a drug may have identical physicochemical properties, the way in which they may interact with chiral targets at the level of the cell will give rise to different pharmacod)mamic and pharmacokinetic properties. A few simple examples will illustrate how taste and olfactory receptors can differentiate between enantiomers. Thus R-carvone tastes like spearmint whereas the S-isomer tastes like caraway. Similarly, R-limolene smells like lemon whereas the S-enantiomer tastes of orange. 

Conclusion The enantiomers of a racemate can differ sufficiently in their pharmacodynamic and pharmacokinetic properties to constitute two distinct drugs. 

The pharmacokinetics of etodolac have been extensively studied [4, 37-38]. Etodolac possesses a chiral center, and it has been established that the (S)-(+)-etodolac enantiomer possesses almost all of the anti-inflammatoiy property. Pharmacokinetic properties of the non-stereospecific and stereospecific etodolac are described in the following sections... 

Disposition in the Body. Well absorbed after oral administration. The 5-enantiomer is stated to be considerably more potent as an anticoagulant than the R-form but there appears to be little difference in pharmacokinetic properties. Phenprocoumon is thought to be excreted almost entirely as a glucuronide conjugate with less than 10% of the dose as unchanged drug. 

Ferroquine possesses planar chirality due to the non-symmetrical 1,2-substitution of the ferrocene entity, and the pure enantiomers (+)35 and (—)35 were obtained by enzymatic resolution using the Candida rugosa lipase as a biocatalyst. The enantiomeric purity levels exceed 98%. However, the two optical isomers display identical activity in vitro at the nanomolecular level. In vivo, however, either of the enantiomers alone is less active than the racemic mixture against both chloroquine-sensitive and chloroquine-resistant strains. In addition, (4-)35 displays better curative effects than (—)35, suggesting different pharmacokinetic properties. The reasons for the enhanced behavior of racemic ferroquine have not yet been elucidated. It is still not clear whether 35 is oxidized by the parasite to give the ferricinium ion, thus initiating Fenton-type reactivity. Such a hypothesis is reasonable, given that reactive oxidative species can escalate in cancer cells due to the malfunction of mitochondria. ... 

Stereochemistry of the local anesthetics, however, plays an important role in their observed toxicity and pharmacokinetic properties. For example, ropivacaine and levobupivacaine, the only optically active local anesthetics currently being marketed, have considerably lower cardiac toxicities than their close structural analogue, bupivacaine (45). Furthermore, the degree of separation between motor and sensory blockade is more apparent with ropivacaine and levobupivacaine relative to bupivacaine at a lower end of the dosage scale (46). Thus, the observed cardiac toxicity of bupivacaine has been attributed to the F -( + )-bupivacaine enantiomer (41,42,43). The exact mechanisms for this enantiomeric... 

It has become abundantly clear that the stereoselective actions associated with the enantiomeric constituents of a racemic drug can differ markedly in their pharmacodynamic or pharmacokinetic properties [2-5]. These factors can lead to much concern, especially if a drug containing a potentially resolvable center is marketed as a racemic mixture. This situation is not invariably bad, but it is clear that a racemate should not be administered when a clear-cut advantage exists with the use of a resolved enantiomer [6]. An excellent discussion regarding the possible selection of a resolved enantiomer over a racemate, from both a practical and a regulatory viewpoint, has been provided by De Camp [7]. 

Many pharmaceutical excipients consist of chiral molecules. The common chiral excipients are listed in Table 3 [54]. When a chiral excipient is used in a formulation, the dissolution rate of the opposite enantiomers may differ, because the interactions between the excipient and each enantiomer are diastereomeric and may therefore differ. In the field of chromatography, the different strengths of the diastereomeric interactions form the basis of enantiomeric separation on a chiral column. Because the opposite enantiomer may exhibit different pharmacological, toxicological, or pharmacokinetic properties, it is of practical value to compare the release rate of the opposite enantiomers from a formulation containing a chiral excipient. 

The most important differences between enantiomers occur in drug receptor interactions. Indeed, Lehmann [34] has stated, the stereoselectivity displayed by pharmacological systems constitutes the best evidence that receptors exist and that they incorporate concrete molecular entities as integral components of their active-sites. In contrast to the pharmacokinetic properties of a pair of enantiomers (Sec. 4), differences in pharmacodynamic activity tend to be more marked, and eudismic ratios of 100 to 1000 are not uncommon. 

Some chiral metabolites of antimalarial drugs possess significant levels of antimalarial activity in comparison to parent drug. For example, the main circulating metabolite of halofantrine, ( )-desbutylhalofantrine, possesses an in vitro level of antimalarial activity similar to that of parent drug [42]. The enantiomers of this metabolite also share similar antimalarial activities in vitro. Stereoselectivity in pharmacokinetic properties of these chiral metabolites could influence an assessment of antimalarial activities. On the other hand, neither of the enantiomers of the major 4-carboxylic acid metabolite of mefloquine possesses antimalarial activity [43]. 

Ondansetron is a chiral antiemetic drug used to prevent nausea and vomiting associated with use of antineoplastics. Although chiral assays have been developed for the drug [228,229], in our search we could not find any literature that described the pharmacokinetic properties of the enantiomers of the drug in humans. 

Enantiomers of compounds, in which chiral center is distant from 4-quinolone ring, such as lomefloxacin, clinafloxacin, gatifloxacin, and tosufloxacin, do not show significant differences in antibacterial activity and pharmacokinetic properties [5-9],... 

During preclinical assessment of an enantiometric mixture, it may be important to determine to which of these three classes it belongs. The pharmacological and toxicological properties of the individual isomers should be characterized. The pharmacokinetic profile of each isomer should be characterized in animal models with regard to disposition and interconversion. It is not at all unusual for each enantiomer to have a completely different pharmacokinetic behavior. 

Bishydroxycoumarin (dicoumarol) is a natural occurring anticoagulant found in sweet clover. A number of coumarin derivatives have been synthesized as anticoagulants, warfarin, phenprocoumon and acenocoumarol being most frequently used. The nonpolar carbon substituent at the 3 position required for activity is asymmetrical. The enantiomers differ in both pharmacokinetic and pharmacodynamic properties. The coumarins are marketed as racemic mixtures. 

A direct consequence of the stereospecific nature of many metabolic processes is that racemic modifications must be treated as though they contained two different drugs, each with its own pharmacokinetic and pharmacodynamic properties. Investigation of these properties must include an investigation of the metabolites of each of the enantiomers of the drug. Furthermore, if a drug is going to be administered in the form of a racemic modification, the metabolism of the racemic modification must also be determined, since this could be different from that observed when the pure enantiomers are administered separately. 

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