Racemates drugs administered

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. 

One further point which should be considered is the importance of dose size. Because of the (R) — (S) conversion, the dosage of the (S) form administered may be as much as two or three times the anticipated dose. One can visualize an elderly 90 lb lady, with decreased renal function, who is administered a racemic drug. She receives the normal dose calculated for a 150 lb person (because of the way the tablets are made up). Because of decreased renal function and increased retention there is time for all the (i ) enantiomer to be converted to the (S) enantiomer. Effectively, she will receive three times the needed dose of the active drug and the area under the dose—time curve will be much greater. It is hardly surprising that adverse side effects sometimes occur.99... 

More than half of all drugs on the market are asymmetric molecules. Many of these are administered as racemates. Since biological recognition systems are based on optically active molecules, the two enantiomers of a racemic drug may interact by different mechanisms with these systems. One of the enantiomers may exert pharmacologically different or unwanted side effects [1-3]. The same is true for racemic pesticides and herbicides often only one of the enantiomers possesses the desired activity. 

Levy and others (35,36) have developed an extensive literature which demonstrates in animal models of disease that the pharmacodynamics of a number of drugs are altered, even after controlling for pharmacokinetic changes. Studies with drugs administered as racemic mixtures in humans with renal dysfunction, hepatic dysfunction, and other disease states that address the issue of stereoselective pharmacodynamics are lacking. However, the cited animal studies suggest that such a line of investigation would be fruitful. 

Conjugation enzymes may show stereospecificity toward enantiomers when a racemic drug is administered. The metabolite pattern of the... 

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]. 

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]. 

For nilvadipine, after administering 4 mg of racemic drug orally to three healthy volunteers, plasma concentrations of the more active (-I-) enantiomer were higher than antipode (Table 7) [72]. Stereoselectivity was greater than seen for nitrendipine or amlodipine, as the (- -) (—) AUC and Cniax ratios were each 2.8. 

Table 14). A subsequent study [85] after the multiple dose administration of the racemate, however, showed an opposite stereoselectivity relative to that found after the administration of the single doses of the enantiomers separately [84] the plasma concentrations of S-propafenone were higher than those of its antipode when the racemate was administered. Further studies [133] after the administration of the separate enantiomers or the racemate to the same subjects demonstrated that the oral clearance of the R enantiomer is almost the same whether the administered drug is the enantiomer or the racemate. However, the oral clearance of the S enantiomer is significantly reduced in the presence of the other isomer (Table 14). This was attributed to an enantiomer-enantiomer interaction at the level of metabolism where R-propafenone reduces the metabolism of the S enantiomer [85]. 

A classic method of demonstrating enantioselective first-pass metabolism is to administer the racemic drug orally and i.v. in a crossover study and then evaluate the PK of each enantiomer using a stereospecific assay. Stereoselective first-pass metabolism is indicated by significantly different absolute bioavailabilities of the enantiomers. This approach was used to establish low enantioselective first-pass metabolism of ketoprofen [56] and high enantioselectivity of propranolol [38,42] and verapamil [44,45,53]. Enantioselective metabolism of propranolol and verapamil has been studied extensively and found to be influenced by age and gender [40,50]. With verapamil, changes in plasma enantiomeric ratios after administration... 

The combination of stable isotopes and MS gives a powerful tool with extra features for the study of drug metabolism. For example, luilike natural products, most synthetic drugs are racemic mixtures. Administering a racemate with one enantiomer labeled with stable isotopes can show up any en-antioselective route of metabolism. It is important to administer a racemic mixture because the... 

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]. 

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