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Stereopharmacokinetics: Past, present and future
2283
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Stereopharmacokineties: Past, Present and Future Piotrovskii, V.K. Center for preventive Medicine, USSR Ministry of Health and Welfare, 101953 Moscow, USSR
Many drugs in clinical use and under experimental investigations are chiral, i.e. contain one or more asymmetric carbon atoms. There is a lot of evidences of remarkable differences in pharmacological properties of enantiomers. However, they are usually used as racemic mixtures. If enantiomers would be i¢:entical in their pharmacokinetics there would be no problems, but generally this is not the case. Enzymes and other proteins binding sites are chiral and this accounts for the enantioselectivity in drug disposition in the organism. This phenomenon is the basis for stereopharmacokinetics (SPK) which is a new branch of pharmacokinetics dealing with specific aspects of influence of the drugs chirality on their absorption, distribution and elimination. Past. Since enantiomers separation and quantitation is a very complex analytical problem there were only limited data on pharmacokinetic stereoselectivity and due to this stereopharmacokinetic problems were not n,. focus for years. But the last decade provides the great progress in analytical methods for separate determination of drug enantiomers in biological fluids mainly by means of the liquid chromatography. Several examples showing significant stereoselectivity in pharmacokinetics of some drugs were also published. Present. Numerical examples appear in the literature during the last several years demonstrating stereoselectivity in pharmacokinetics and pharmacodynamics of a lot of drugs from different groups (beta-adrenoceptor blockers, calcium antagonists, psychotropic agents, non-steroidal antiinflammatory drugs, etc.). Several reviews were published, and SPK became one of the most popular field of scientific activity, the true growth point of modern pharmacokinetics. Future. The period of accumulating of new and new empirical data should be changed by a period of synthesis and generalization. Incorporating stereoph~acokinetic methods into the routine experimental and clinical studies will provide more systematic information and will help to formulate basic principles which can predict the value of enantiomeric differences for new drugs on the basis of their chemical structures. One may assume that stereopharmacokinetic problems will disappear when pure enantiomers will be used exclusively. For this, however, a lot of technological problems are to be get over, and, of course, enantiomerically pure drugs will be much more expensive than racemic. Moreover, biotransformation of some achk~ &ugs produces chiral metabolites which may be pharmacologically active. And SPK remains important even in the un~:~sti~= situation c,f not using racemic drugs. The more real perspective consists in applying SPK to clarify the lack of relationships between drug pharmacodynamics and pharmacokinetics which may be the result of measuring racemat I concentrations instead of concentrations of active enantiomers of drugs armd their metabolites. Using SPK in this context may provide data on effective concentrations of active substances and, in turn, may extend the applicability of therapeutic drug monitoring (which should be enantioselective) in the optim~tion of drug therapy.
P.fr.196 1 Stereoselective pharmacokinetics of oral and intravenous nitrendipine in healthy subjects Soons, P.A., Roosemalen, M.C.M. and Breimer, D.D. Division of Pharmacology, Center for Bio.Pharmaceutical Sciences, Leiden University, P.O. Box 9503, 2300 RA £ olden, The Netherlands
The pharmacokinetics of nitrendipine (NIT), a chiral dihydropyridine calcium entry blocker in healthy subjects have been reported by others (Mikus et al., 1987) and by us (Soons et al., 1~89). Stereoselectivity in NIT pharmacokinetics could not be .~sessed at that time because of the lack of analytical methodology. Recent data indicate stereoselectivity in the disposition of orally administered pseudo-racemic NIT (Mikus et al., 1989). We have
....P~ifr2__5~ 195
Stereopharmacokineties: Past, Present and Future Piotrovskii, V.K. Center for preventive Medicine, USSR Ministry of Health and Welfare, 101953 Moscow, USSR
Many drugs in clinical use and under experimental investigations are chiral, i.e. contain one or more asymmetric carbon atoms. There is a lot of evidences of remarkable differences in pharmacological properties of enantiomers. However, they are usually used as racemic mixtures. If enantiomers would be i¢:entical in their pharmacokinetics there would be no problems, but generally this is not the case. Enzymes and other proteins binding sites are chiral and this accounts for the enantioselectivity in drug disposition in the organism. This phenomenon is the basis for stereopharmacokinetics (SPK) which is a new branch of pharmacokinetics dealing with specific aspects of influence of the drugs chirality on their absorption, distribution and elimination. Past. Since enantiomers separation and quantitation is a very complex analytical problem there were only limited data on pharmacokinetic stereoselectivity and due to this stereopharmacokinetic problems were not n,. focus for years. But the last decade provides the great progress in analytical methods for separate determination of drug enantiomers in biological fluids mainly by means of the liquid chromatography. Several examples showing significant stereoselectivity in pharmacokinetics of some drugs were also published. Present. Numerical examples appear in the literature during the last several years demonstrating stereoselectivity in pharmacokinetics and pharmacodynamics of a lot of drugs from different groups (beta-adrenoceptor blockers, calcium antagonists, psychotropic agents, non-steroidal antiinflammatory drugs, etc.). Several reviews were published, and SPK became one of the most popular field of scientific activity, the true growth point of modern pharmacokinetics. Future. The period of accumulating of new and new empirical data should be changed by a period of synthesis and generalization. Incorporating stereoph~acokinetic methods into the routine experimental and clinical studies will provide more systematic information and will help to formulate basic principles which can predict the value of enantiomeric differences for new drugs on the basis of their chemical structures. One may assume that stereopharmacokinetic problems will disappear when pure enantiomers will be used exclusively. For this, however, a lot of technological problems are to be get over, and, of course, enantiomerically pure drugs will be much more expensive than racemic. Moreover, biotransformation of some achk~ &ugs produces chiral metabolites which may be pharmacologically active. And SPK remains important even in the un~:~sti~= situation c,f not using racemic drugs. The more real perspective consists in applying SPK to clarify the lack of relationships between drug pharmacodynamics and pharmacokinetics which may be the result of measuring racemat I concentrations instead of concentrations of active enantiomers of drugs armd their metabolites. Using SPK in this context may provide data on effective concentrations of active substances and, in turn, may extend the applicability of therapeutic drug monitoring (which should be enantioselective) in the optim~tion of drug therapy.
P.fr.196 1 Stereoselective pharmacokinetics of oral and intravenous nitrendipine in healthy subjects Soons, P.A., Roosemalen, M.C.M. and Breimer, D.D. Division of Pharmacology, Center for Bio.Pharmaceutical Sciences, Leiden University, P.O. Box 9503, 2300 RA £ olden, The Netherlands
The pharmacokinetics of nitrendipine (NIT), a chiral dihydropyridine calcium entry blocker in healthy subjects have been reported by others (Mikus et al., 1987) and by us (Soons et al., 1~89). Stereoselectivity in NIT pharmacokinetics could not be .~sessed at that time because of the lack of analytical methodology. Recent data indicate stereoselectivity in the disposition of orally administered pseudo-racemic NIT (Mikus et al., 1989). We have