Pharmacokinetics racemic drugs

Which bioequivalence study for racemic drug , Eur. J. Drug Metab. Pharmacokinet., 23, 166 (1998). 

For those drugs that are administered as the racemate, each enantiomer needs lo be monitored separately yet simultaneously, since metabolism, excretion or clearance may be radically different for the two enantiomers. Further complicating drug profiles for chiral drugs is that often the pharmacody namics and pharmacokinetics of the racemic drug is not just the sum of Ihe profiles of the individual enantiomers. 

Currently there is a trend toward the synthesis and large-scale production of a single active enantiomer in the pharmaceutical industry [61-63]. In addition, in some cases a racemic drug formulation may contain an enantiomer that will be more potent (pharmacologically active) than the other enantiomer(s). For example, carvedilol, a drug that interacts with adrenoceptors, has one chiral center yielding two enantiomers. The (-)-enantiomer is a potent beta-receptor blocker while the (-i-)-enantiomer is about 100-fold weaker at the beta-receptor. Ketamine is an intravenous anesthetic where the (+)-enantiomer is more potent and less toxic than the (-)-enantiomer. Furthermore, the possibility of in vivo chiral inversion—that is, prochiral chiral, chiral nonchiral, chiral diastereoisomer, and chiral chiral transformations—could create critical issues in the interpretation of the metabolism and pharmacokinetics of the drug. Therefore, selective analytical methods for separations of enantionmers and diastereomers, where applicable, are inherently important. 

Similar to many other cases of biologically active compounds, stereochemistry influences the pharmacological effect of a chiral drug. This can be explained by the fact that there is only one energeticaUy favorable (specific) interaction of an active molecule with its receptor, both being chiral structures. Qualitative and quantitative differences are caused by different receptor affinities as demonstrated in Fig, 1 (1). The metabolism (biotransformation) of drugs is mainly caused by enzymes, which are chiral macromolecules and discriminate between substrate molecules of different stereochemistry, This may result in metabolites of different activity and in different pharmacokinetics, resorption, and excretion. Therefore, racemic drugs should be looked on as a 1 1 mixture of two different compounds. 

For the clinical pharmacologist, neither of these racemic drug mixtures is problematic for drug therapy in the clinic if a pharmacodynamic endpoint (e.g., decrease in blood pressure with propranolol or improvement in arthritic pain with ibuprofen) is used to establish drug dose. However, to effectively characterize the pharmacokinetics of the active isomer, an endeavor that may be useful during drug development, administration, and/or specific determination of the active isomer is required. Such data... 

In a few cases, the option of preparing tailor-made CSPs for a particular racemic structure has been applied. For example, we prepared on an empirical basis a particular polysaccharide-based CSP for the separation of the enantiomers of the enantiomers of the LTD4 antagonist iralukast and of the antimalaria agent benflumethol [87]. These two racemic drugs were only poorly resolved on the commercially available polysacharide-based phases whereas an excellent separation was obtained on the carbamate derivative of cellulose obtained from cellulose and 3-chloro-4-methylphe-nylisocyanate. The prepared CSP was also used to perform pharmacokinetic studies. 

Srinivas, N. R. Clinical pharmacokinetic data of racemic drugs obtained by the indirect method following precolumn diastereomer formation Is the influence of racemization during chiral derivatization significant Biomed. Chromatogr, 2004, 18, 343-349. 

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]. 

Weber-Grandke, H. Hahn, G. Mutschler, E. Mohrke, W. Langguth, P. Spahn-Langguth, H. The pharmacokinetics of tranylcypromine enantiomers in healthy subjects after oral administration of racemic drug and the single enantiomers. Br. J. Clin. Pharmacol. 1993, 36, 363-365. 

Because many of the pharmaceutical excipients used in the formulation of racemic drugs are chiral and optically pure, there is a potential for the stereoselective interaction of the enantiomers with the chiral matrix included in the formulation. For example, enantioselective pH-dependent release of tiaprofenic acid enantiomers from a sustained release formulation containing microcrystalline cellulose has been reported [260]. The differential release of tiaprofenic acid enantiomers, however, did not alter the pharmacokinetics of the individual enantiomers in rats. The possible effects of chiral excipients on the stereoselective release of racemates are discussed in a separate chapter in this book. 

Alshowaier, I.A. el-Yazigi, A. Ezzat, A. Abd el-Warith, A. Nicholls, P.J. Pharmacokinetics of S- and R-enantiomers of aminoglutethimide following oral administration of racemic drug in breast cancer patients. J. Clin. Pharmacol. 1999, 59, 1136-1142. 

The two enantiomers of a racemic drug may interact with each other at different pharmacokinetic or pharmacodynamic levels. This type of interaction has been studied for atenolol [2] and propranolol [51 53]. For atenolol, there was no pharmacokinetic or pharmacodynamic interaction between the two enantiomers the half-dosed S(—)-atenolol produced the same effect as did the racemic atenolol [2]. Additionally, the plasma concentration-time profiles of S(—)-atenolol were identical after the administration of the racemate and the half-dosed pure enantiomer. On the other hand, both single [51] and multiple [52] dose studies have shown that there is a significant interaction between the enantiomers of propranolol. When administered as pure enantiomer, as opposed to the racemate, R(- -)-propranolol tends to show lower plasma concentrations [52]. However, the kinetics of the more active S(—)-enantiomer appear to be the same whether it is administered as a pure enantiomer or racemate [51-53]. 

A thorough understanding of the pharmacokinetics of drugs is essential in the determination of safe and effective dosing regimens. In the case of a racemic drug or stereochemically pure enantiomer this implies knowledge of the in vivo behavior of the stereoisomers. 

Figure 3 Pharmacokinetic/pharmacodynamic relationship and enantiospedfic first-pass metabolism of verapamil. A prototype category HI racemic drug. Unlike propranolol, with verapamil the EC50 value for the PR prolongation, determined on the basis of the nonenantiospecific assay, is higher after the oral dose than after the intravenous dose (upper panel). This is attributed to the greater first-pass metabolism of the more active S-enantiomer (lower panel). Slowing the oral input rate by switching from an immediate- (IR) to a sustained-release (SR) formulation results in a significant ( = P < 0.05 by paired t test) decrease in the proportion of the more active S-enantiomer at maximum concentration (Cmax R + S). (From Ref 26, with permission.)...

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