Τόμος 7 (1989) – Τεύχος 2 – Άρθρο 3 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Ελληνική Έκδοση – Volume 7 (1989) – Issue 2 – Article 3 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-Greek Edition

C. T. PLESSAS, S. T. PLESSAS AND A. BENAKIS

7: 86-110 (1989)

PHARMAKON-Press: Epitheorese Klin. Farmakol. Farmakokinet.

7: 86-110 (1989)

Biological macromolecules, such as receptors, enzymes, carrier molecules, etc., possess a discriminatory capacity which allows them to differentiate between the enantiomers of bioactive agents (e.g. neuro­transmitters, hormones, drugs, etc.). This sele­ctive differentiation, based on a stereochemical complementariΣy, is easily understood accor­ding to the three-point interaction concept (fig. 1). Drug enantiomers often exhibit greatly distinct affinities at binding sites (i.e. the receptor site on the receptor molecule, or the active site on the enzyme). As a consequence, enantiomers may differ in their pharmacokine­tics and metabolism; therefore, after admini­stration of a racemic drug, concentration differences of the enantiomers may be measu­red. Drug absorption may exhibit stereoselectivi­ty in the case of enantiomers which are actively transported across the intestinal mucosa (e.g. methotrexate) (12). Drug enantiomers may differ either in tissue up take (e.g. stereoselective uptake by the heart of the rats of ·S(-)­propranolol and extravascular binding of S(­propranolol in the dog) (13, 14) or in plasma protein binding. The diazepam site (II) of human serum albumin exhibits a high stereoselectivity in binding to drug enantiomers (15, 21), such as tryptophan (17), oxazepam hemisuccinate (18), 3-methyldiazeρam (20). Stereoselective is also the binding of basic drugs to α₁-acid glycoprotein (15, 21); this is the case e.g. of propranolol (22, 23) and disopyramide (24). The stereoselective biotransformations of drugs may be classified as (a) substrate stereoselecti­vity (only one enantiomer is converted by the enzyme) (fig. 3). shown e.g. for warfarin, phenprocoumon (34) (fig. 4), mephenytoin (35, 36) (fig. 5) and 3ΡΡΡ (33); (b) product stereo-selectivity (i.e. differential formation of two enantiomeric metabolites from a single pro-chiral substrate) noticed e.g. for diphenylhydantoin (fig. 6) (37) and 4-tοlyl ethyl sulfide (fig. 2) (29, 30); (c) substrate-product stereoselecti­vity (i.e. differential formation of one of the possible diastereomeric metabolites) (fig. 7) demonstrated e.g. for nicotine (fig. 8 and 9) (30); and (d) enzymatic inversion of the confi­guration of only one of the enantiomers to the other isomer (fig. 10), as in the case of non-steroidal anti-inflammatory drugs derivatives of 2-arylρrορionic acid (40-43). Significant stereo-selective first-pass metabolism has been de­monstrated e.g. for verapamil (44-49), propra­nolol (fig. 11) (50, 51) and metoprolol, resulting in differences in systemic availability for enan­tiomeric pairs of high extraction ratio drugs. Stereoselectivity in drug metabolism may be influenced by enzyme induction or inhibition (26-28); this is the case e.g. of the in vitro glucuronidation of oxazepam enantiomers mar­kedly influenced by a variety of inducers. The racemic drug administration may leadto enan­tiomer-enantiomer interactions noticed e.g. for amphetamine (57), p-chloroamphetamine (58), nicotine (59), methadone (60), 3ΡΡΡ (26, 33), methorphan (61), propoxyphene (62), propra­nolol (63), and ibuprofen (64); one enantiomer may compete with the other for binding at plasma protein binding sites, the enzyme active sites, or at receptor sites. Enantiomer-drug interactions may also occur stereoselectivity; such interactions are demonstrated between warfarin enantiomers and a number of drugs including phenylbutazone (fig. 12) (65-68), sulphinpyrazone (69), metronidazole (70), co­trimoxazole (71), clofibrate (72), disulfiram (73), quinalbarbitone (74), tienilic acid (75) and cimetidine (76); leadint to augmentation of the hypoprothrombinaemic response, through ste­reoselective inhibition of the S(-)-warfarin me­tabolism, associated with concurrent stereose­lective displacement of this enantiomer from plasma protein binding sites. All these inter­actions do not have significant clinical con­sequences when patients begin treatment with both drugs, but the dose of warfarin must be lower than in the absence of the second drug. Problems arise when the second drug is added in patients who are already under treatment of warfarin, as this may lead to haemorrhagic episodes. Genetic factors may play an impor­tant role in stereoselective metabolism of certain drugs, such as debrisoquine (78, 79), metoprolol (fig. 13) (54, 80), bufaralol (fig. 14 and 15) (81), mephenytoin (82-85) and propa­fenone (81), and human populations exhibit bimodal polymorphism (i.e. some subjects are poor metabolisers and some other extensive metabolisers), controlled by the debrisoquine/ sparteine.

1. Ariens, E.J.: Stereoselectivity, a natural aspect of molecular biology: Α blind spot in clinical pharmacology and pharmacokirietics. Eur. J. Drug Metab. Pharmacokinet. 13: 307 (1988)
2. Ariens, E.J.: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmaco­logy. J. Clin. Pharmacol. 26: 663 (1984)
3. Lam, Y.W.F.: Stereoselectivity: an issue of significant importance in clinical pharmacology. Pharmacotherapy 8: 147 (1988)
4. Plesses, C.Τ., Plessas, S.T., Benakis, Α.: Stereochemistry of drugs and bioactive agents. Klin. Farmakol. Farmakokinet. 7: 15 (1989)
5. Plessas, C.T., Plessas, S.T., Benakis, Α.: Drug stereo-chemistry and stereoselectivity: Implications in clinical pharmacology. Kiln. Farmakal. Farmakokinet. int. Ed 2: 67 (1988)