Pharmacokinetics enantiomers

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. 

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. 

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. 

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

Generic applications for chiral medicinal products should be supported by bioequivalence studies using enantiospecific bioanalytical methods unless both products contain the same, stable, single enantiomer or both products contain a racemate where both enantiomers show linear pharmacokinetics. 

Where the drug studied is a racemate, the pharmacokinetics, including potential interconversion, of the individual enantiomers should be investigated in Phase I clinical studies. Phase I or II data in the target population should indicate whether an achiral assay, or monitoring of only one optical isomer where a fixed ratio is confirmed, will be adequate for pharmacokinetic evaluation. If the racemate has already been marketed and the sponsor wishes to develop the single enantiomer, additional studies should include determination of any conversion to the other isomer and whether there is any difference in pharmacokinetics between the single enantiomer administered alone or as part of the racemate. 

With the increased popularity of LC-MS, the problem of overlapping enantiomer peaks from other amino acids has largely been resolved. The mass spectrometer can act as an additional dimension of separation (based on mass to charge ratio). Thus, only amino acids having the same mass-to-charge ratio must be separated achirally (see Desai and Armstrong, 2004). This additional dimension of separation also has implications for the applications in the matrices discussed previously. With the ability of the mass spectrometer to discriminate on the basis of mass, this lessens the need for complete achiral separation. For example, an LC-MS method was recently developed to study the pharmacokinetics of theanine enantiomers in rat plasma and urine without an achiral separation before the enantiomeric separation (Desai et al., 2005). In such matrices, proteins must still be removed by appropriate sample preparation. 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

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. 

Dexrazoxane was also hydrolyzed enzymatically in the liver and kidney by dihydropyrimidine aminohydrolase. This enzyme could hydrolyze one but not a second ring of this molecule. Levrazoxane, the enantiomer of dexrazoxane, was also hydrolyzed enzymatically by DHPase in liver homogenates, but at a rate 4.5-fold slower [136], However, in vivo studies in rats dosed with razoxane (the racemic mixture of levrazoxane and dexrazoxane) revealed only a relatively small difference in elimination of the two enantiomers. This suggests that distribution and excretion reduced the impact of stereoselective biotransformation on the pharmacokinetics of these two enantiomers [137]. 

Svensson, U.S., Alin, H., Karlsson, M.O., Bergqvist, Y., and Ashton, M., Population pharmacokinetic and pharmacodjmamic modeling of artemisinin and mefloquine enantiomers in patients with falciparum malaria, Eur.. Clin. Pharmacol, 58, 339-351, 2002. 

Eriksson, T., Bjorkman, S., Roth, B., and Hoglund, P., Intravenous formulations of the enantiomers of thalidomide pharmacokinetic and initial pharmacodynamic characterization in man, /. Pharm. Pharmacol., 52, 807-817, 2000. 

S(-) enantiomer occurs naturally, and the R(+) enantiomer is synthetic (Kalix 1992). Pharmacokinetics... 

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). 

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