Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology

Abstract

The significance of stereochemistry in therapeutic action is outlined and elucidated. Often only one isomer is therapeutically active, but this does not mean that the other is really inactive. It may very well contribute to the side-effects. The therapeutically non-active isomer in a racemate should be regarded as an impurity (50% or more). It is emphasized how in clinical pharmacology, and particularly in pharmacokinetics, neglect of stereoselectivity in action leads to the performance of expensive "highly sophisticated scientific nonsense". This also holds true in the development and marketing of new drugs as exemplified by various "pseudo-hybrid" drugs now reaching the clinic.

Stereoselective disposition of mexiletine in man.

“…However, stereoisomers invariably do have distinct biological properties (Ariens, 1984). Therefore, it is unlikely that the enantiomers of mexiletine are identical in all of their effects.…”

The pharmacokinetics of the enantiomers of flurbiprofen in patients with rheumatoid arthritis.

“…It is well documented that enantiomers can have different pharmacological actions and disposition properties (Ariens, 1984;Ariens & Wuis, 1987;Drayer, 1986). The issue with flurbiprofen and the other aryl propionic acids is complicated further by a metabolic inversion of the pharmacologically inactive R(-)-enantiomer to the active S(+)-enantiomer (Hutt & Caldwell, 1983;Caldwell et al, 1988a,b).…”

The Accepted “Clinical Interaction Model”: A Special Case of Reality

“…Yes [53,56,[67][68][69] Can new antibiotics be developed from the already known non-antibiotics Yes [19,54,55,64,[70][71][72][73][74] Can "purer" drugs be developed by utilizing stereo-specificity? Up until 1985, 85% of all drugs were mixtures Yes [71,72,75,[76][77][78] Will this polypharmacy have any influence on the pharmacokinetics or pharmacodynamics of clinical treatment for the patient/host Yes [60,75,[79][80][81][82][83][84][85][86] up until now, have not been able to treat. The demonstration of the antimicrobial activity of non-antibiotics raises a number of exciting perspectives.…”