Enantiomers pharmacodynamic

Similarity/differences between enantiomers Pharmacodynamics (pharmacology and toxicity) Metabolic disposition... 

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. 

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. 

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. 

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

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. 

The second generation H -receptor antagonist cetirizine is a reacemate consisting of equal quantities of 2 enantiomers, levocetirizine [(R)-enantiomer] and dextrocetirizine [(S)-enantiomer]. In vitro and human pharmacodynamic studies have provided evidence that levocetirizine is the more active enantiomer, accounting for most or all clinical antihistaminic activity of racemic cetirizine this activity of levocetirizine is seen at half the dose of cetirizine. 

Chan K, Lo AC, Yeung JH, Woo KS. The effects of danshen Salvia miltior-rhiza) on pharmacodynamics and pharmacokinetics of warfarin enantiomers in rats. J Pharm Pharmacol 1995 47 402-406. 

Ho PC, Ghose K, Saville D, Wanwimolruk S. Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in healthy volunteers. Eur J Clin Pharmacol 2000 56(9-10) 693-698. 

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. 

Pharmacokinetic—pharmacodynamic characterization of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites.53... 

At the cellular level, the various types of receptor, transporter, enzyme and ion channel 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 pharmacodynamic 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. 

For BA studies, measurement of individual enantiomers may be important. For BE studies, this guidance recommends measurement of the racemate using an achiral assay. Measurement of individual enantiomers in BE studies is recommended only when all of the following conditions are met (1) The enantiomers exhibit different pharmacodynamic characteristics. (2) The enantiomers exhibit different pharmacokinetic characteristics. (3) Primary efficacy and safety activity resides with the minor enantiomer. (4) Nonlinear absorption is present (as expressed by a change in the enantiomer concentration ratio with change in the input rate of the drug) for at least one of the enantiomers. In such cases, BE criteria should be applied to the enantiomers separately. 

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. 

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. 

Jonkers RE, Koopmans RP, Portier EJ, van Boxtel CJ. 1991. Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers. J Pharmacol Exp Ther 256 959-966. 

Mandema JW, Heijligers-Feijen CD, Tukker E, De Boer AG, Danhof M. 1992a. Modeling of the effect site equilibration kinetics and pharmacodynamics of racemic baclofen and its enantiomers using quantitative EEG effect measures. J Pharmacol Exp Ther 261 88-95. 

An example from our own laboratory is the methylphenidate bioanalyti-cal chiral LC-MS/MS assay in support of toxicokinetics (TK) and PK studies (vide infra). Attention-deflcit hyperactivity disorder (ADHD) is a recognized medical problem characterized by symptoms of inattention, hyperactivity, and impulsivity. Methylphenidate (MPH Ritalin methyl-alpha-phenyl-2-piperid-inacetate hydrochloride) is prescribed for the treatment of ADHD. MPH has two chiral centers yielding enantiomers with distinct pharmacokinetic and pharmacodynamic properties in humans. It is known that the t/-threo [2R,2 R]-MPH (i.e., (-i-)-threo) exhibits greater pharmacological activity than the... 

The important anticoagulant drug warfarin is chiral and is administered cimically as the racemic mixture. Significant pharmacodynamic and pharmacokinetic differences between the enantiomers have generated considerable interest in the stereochemical aspects of this drug (145),... 

Yacobi, A., Lai, Chii-Ming, and Levy, G, (1984). Pharmacokinetic and pharmacodynamic studies of acute interaction between Warfarin enantiomers and Metronidazol. /. Pharmacol Exp, Ther., 232 72-79,... 

D. E. Drayer, Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans An overview, Clin. Pharmacol. Then, 40 125-133 (1986). 

The single stereogenic or chiral center in the chemical structure of verapamil results in two stereoisomers of verapamil S(-)-verapamil and R(+)-verapamil (Fig. 1). These enantiomers have different pharmacokinetic and pharmacodynamic properties (3,6-9). Although both enantiomers have similar types of pharmacologic activity, the S enantiomer has been shown to be the more potent with respect to several of the effects (3,6-8). 

This chapter reviews the pharmacokinetics and pharmacodynamics of the enantiomers of verapamil and examines their impact on verapamil bioavailability. In addition, new information on the influence of product formulation on the differential bioavailabiUty of the enantiomers of verapamil is presented and discussed. 

The two stereoisomers of verapamil differ extensively in their pharmacodynamics. The S enantiomer is the more pharmacologically active of the two relative to the cardiovascular system (3,6-9). The cardiovascular pharmacod maniic effects and relative potency of S- and R-verapamil are summarized in Table 1. 

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