Pharmacokinetic profile, enantiomers

The separation of enantiomers is a very important topic to the pharmaceutical industry. It is well recognized that the biological activities and bioavailabilities of enantiomers often differ [1]. To further complicate matters, the pharmacokinetic profile of the racemate is often not just the sum of the profiles of the individual enantiomers. In many cases, one enantiomer has the desired pharmacological activity, whereas the other enantiomer may be responsible for undesirable side-effects. What often gets lost however is the fact that, in some cases, one enantiomer may be inert and, in many cases, both enantiomers may have therapeutic value, though not for the same disease state. It is also possible for one enantiomer to mediate the harmful effects of the other enantiomer. For instance, in the case of indacrinone, one enantiomer is a diuretic but causes uric acid retention, whereas the other enantiomer causes uric acid elimination. Thus, administration of a mixture of enantiomers, although not necessarily racemic, may have therapeutic value. 

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. 

Williams and Wainer (2002) use examples of two chiral separations to demonstrate their utility in research. In one example, the difference between enantiomers in the competitive displacement of cyclosporine from immobilized P-glycoprotein was studied. In the other, the pharmacokinetic profiles of (+) and (—)-ketamine and (-h) and (—)-norketamine were determined (Williams and Wainer, 2002). 

Due to their almost identical chemical structure, enantiomers represent a subtle class of analogues. Often in a pair of enantiomers, the desired biological activity is concentrated in only one enantiomer. Then, the passage from a racemic mixture to the pure active eutomer - which is usually termed racemic switch - can produce an improved drug. However, in some cases and despite their similar constitution, both enantiomers can have totally different pharmacodynamic or pharmacokinetic profiles. 

Vedaprofen is a propionic acid derivative that, like carprofen and ketoprofen, exists as two enantiomers with different pharmacokinetic profiles in the horse. For example, the plasma disposition of S(-t-)-vedaprofen is characterized by a very rapid decline with a plasma half-life of less than 1 h while R(-)-vedaprofen has a more prolonged elimination phase with a plasma half-life of over 2h (Lees et al 1999). Both enantiomers also accumulate in and exhibit a delayed elimination from inflammatory exudates. In horses, vedaprofen appears to be slightly selective for the COXl enzyme. For example, the median effective concentration for inhibition of serum TXB2 production, which is assumed to be a reflection of COXl activity, was much lower than that for inhibition of inflammatory infiltrate PGE2 production, which is assumed to be a reflection of COX2 activity. Although the results of these studies are promising, there are no published data on the clinical effectiveness and safety of vedaprofen in horses. 

Until recently, all PPIs were marketed as mixtures of enantiomers. However, the development of esomeprazolehas prompted numerous studies to test its therapeutic benefit over that of existing PPIs. Within the last 2 years mae than 40 publications have reported studies involving the use of esomeprazole. Es-omeprazole has an improved pharmacokinetic profile relative to that of omeprazole esomeprazole (20 mg per day for 5 days) had a 70% higher area under the plasma concentrationtime curve than that of omeprazole (20 mg per day for 5 days). The S-isomer of omeprazole (esomeprazole) was found to undergo less metabolism by CYP2C19 than the R-isomer in human liver, this decreased metabolism ac-... 

The recently developed oxadiazoline A-105972 (5i) displayed reasonable cytotoxic activity towards a panel of human cancer cell lines in vitro [38], but its utility in vivo was limited by a short half-life. Further efforts led to the identification of the indolyloxozoline A-259745 (5k) [38] that demonstrated a better pharmacokinetic profile and three times increased survival of tumour bearing nude mice upon oral dosing. The mechanism of tubulin interference and the enantioselective synthesis of A-289099 (5k, S-enantiomer) have been investigated, confirming the competition with colchicine [39]. After the preclinical development no further investigation has been reported. 

In practice, if both optical isomers are of similar potency and have similar pharmacokinetic profiles, it may be useless to proceed to the resolution of the racemic mixture. Such situations are infrequent but may occur. An example is given by the antithrombotic acids 21-X and 21-Y (Fig. 17.9). The corresponding pure enantiomers were first compared with the corresponding racemates for their in vitro activities. 

Use of chiral versus achiral analytical assays has been the subject of much discussion in the literature. If the pharmacokinetic profile is the same for both isomers, or a fixed ratio between the plasma levels of enantiomers is demonstrated in the target population, an achiral assay or an assay that monitors one of the stereoisomers may be sufficient. 

The intracellular half-life of Epivir-TP in peripheral blexxi lymphocytes is 10.5-15.5 hr (49). and in vivo Epivir is primarily excreted uiKhanged by the renal route (52). The 5 -triphosphate of the (- -) enantiomer has a fivefold greater activity against purified HIV-1 reverse transcriptase than Epivir-TP, but it also has a much shorter half-life than Epivir-TP (3.5-7 hr), (49). These data may explain the comparable antiviral potency of the two enantiomers. Clinical studies have shown Epivir to be well tolerated at hi doses, with a good bioavailability and pharmacokinetic profile compared with other nucleoside analogs, and it does not appear to cause bone marrow toxietties in vitro (51,53). 

Most synthetic drugs are available as isomeric mixtures. Individual enantiomers of a chiral drug may significantly differ not only with respect to selectivity of interaction with receptors or enzymes but also bioavailability, metabolic characteristics and excretion rate, therapeutic potency, and toxicity [25-27]. Therefore, the use of a desired stereoisomer of a drug may assure more selective pharmacokinetic profile, improvement of therapeutic indices, and, due to changed metabolic fate, a lower incidence of interactions with other drugs. 

Pharmacokinetic and pharmacodynamic differences between drug isomers present another important issue relating to drug metabolism. Individual enantiomers of drugs administered as racemates show different pharmacokinetic profiles due to differences in metabolic clearance rates and binding affinities to blood plasma proteins [34]. 

For those dmgs that are administered as the racemate, each enantiomer needs to be monitored separately yet simultaneously, since metaboHsm, excretion or clearance maybe radically different for the two enantiomers. Further complicating dmg profiles for chiral dmgs is that often the pharmacodynamics and pharmacokinetics of the racemic dmg is not just the sum of the profiles of the individual enantiomers. 

Pharmacokinetics may also form the basis of a decision on the choice of compound from a series for development. It is not uncommon for a company to take three or four compounds of a series as far as the first study in man and to choose for development the compound that is most attractive from the pharmacokinetic point of view. Similarly, the development of achiral compounds rather than racemic mixtures is generally preferred and it may be necessary to establish whether stereoselective metabolism occurs in man and, if so, which enantiomer has the more desirable profile. 

Esomeprazole (2) is the (5)-enantiomer of racemic omeprazole (1). The former has better pharmacokinetics and pharmacodynamics than the latter and therefore possesses higher efficacy in controlling acid secretion and has a more ideal therapeutic profile. 

The mean concentration-time profiles for each of the four analytes, and for each of the two formulations, generated by this study are shown in Fig. 7. The pharmacokinetic comparisons derived from this study for all four analytes are summarized in Table 4. As can be seen from Fig. 7 and Table 4, a four-way bioequivalence assessment proved both feasible and practical. This study also demonstrated that si ar formulations will produce similar concentration-time profiles for all the enantiomers in the plasma (even given lot-to-lot variability, manufacturing site-to-site variability, and shelf-time variability). 

A non-stereoselective assay is currently acceptable for most pharmacokinetic bioequivalence studies. When the enantiomers have very different pharmacological or metabolic profiles, assays that distinguish between the enantiomers of a chiral API may be appropriate. Stereoselective assay is also preferred when systemic availability of different enantiomers is demonstrated to be non-linear. 

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