Chiral Cognisance: a Road to Safer and More Effective Medicinal Products

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Chiral cognisance: a road to safer and more effective medicinal products

ABSTRACT?A quarter of all synthetic medicinal drugs contain a mixture of equal proportions of two molecules that have the same chemical constitution but differ in the spatial arrangement of their con- stituent atoms such that each is a mirror-image of the other, like the right and left hand. Biologically, receptors which are stereospecific react with only one of the two components of the mixture to produce the desired therapeutic effect, while the other is inactive or may interact with different receptors to cause undesirable, even toxic, effects. Development of syntheses that produce a preponderance of the required form, and efficient separation of mixtures, will result in safer and more effective medicinal products.

Medicinal chemists and pharmacologists have devel- oped highly active and, by implication, selective medicines, yet a quarter of all drugs on the market contain at least 50% of non-therapeutic, potentially harmful chemical ballast. This massive medicinal impurity, the stereoisomeric companion of the therapeutic agent, was already known to Pasteur in 1901. It has been largely and persistently neglected by medicinal chemists, pharmacists and clinical pharmacologists, and is still hardly known to physicians. When a carbon atom in a molecule is linked to four Fig 1. Types of stereoisomers, (a) When four different chemically different groups, its tetrahedric configura- groups are attached to a carbon atom, mirror-image tion can give rise to a mirror-image asymmetry, a type isomers (enantiomers) exist; the order in which the of stereoisomerism (Fig 1). In solution, the stereo- groups occur is specified clockwise (R) or counter- isomers of the molecule are almost identical in their clockwise (S). (b) Compounds with a carbon-carbon physico-chemical properties, except in their behaviour double bond may occur as cis (Z) and trans (E) iso- with regard to polarised light. This is rotated by the mers. isomers in opposite directions, indicated as right (dextro, d) and left (levo, /). A more up-to-date chirality like the right and left hands (Gk chiros, hand). nomenclature is R and S for clockwise and counter- The 1:1 mixture itself is called a racemate; it does not clockwise order in which the different are the of groups change plane polarised light because the oppos- located on the carbon atom tetrahedron effects of the (Fig 1). ing rotatory enantiomers are equally When such carbon compounds are synthesised from balanced. chemical stones dextro- and If hands were to building free in solution, be assembled from a mixture of molecules have an chance of for- in the of levo-rotatory equal fingers presence only left-hand gloves as a mation, producing a 1:1 mixture of two mirror-image mould, nothing but left hands would be formed; simi- isomers. are known as enantiomers and exhibit chiral molecules can be They larly, synthesised in the presence of suitable stereospecific catalysts. In biology, it is which the role of E J ARIENS, MD, PhD enzymes play (substrate) stereoselective and Emeritus Professor, Institute of Pharmacology and (product) stereospecific catalysts. Since amino acids and Toxicology, University of Nijmegen, The Netherlands sugars, the major building stones of bio- E W PhD WUIS, logical macromolecules, are themselves chiral, the pro- of Clinical teins and Department Pharmacy, glycoproteins which constitute enzymes, St The Netherlands University Hospital Nijmegen Radboud, receptors, carrier molecules etc are also chiral. If the

Journal of the Royal College of Physicians of London Vol. 28 No. 5 September/October 1994 E J Ariens and E W Wuis

Fig 2. Chirality of drugs and their application as single isomers or racemates. Most natural and semisynthetic products are chiral and marketed as single isomers; most chiral synthetic products are marketed as racemates.

therapeutic receptor accepts, say, /-isomers only, the d- of the mostly therapeutically useless but potentially isomers of a racemic drug will be inactive or interact toxic isomer(s), the isomeric ballast, has largely been with other stereospecific receptors which may produce neglected; although that is convenient for the drug undesirable effects. industry, it is not good for patients. With few excep- The degree of stereospecificity depends on the posi- tions, the enantiomers in a racemic mixture must be tion of the chiral centre in the molecule. A high regarded as two fundamentally different compounds, degree of stereospecificity means that the chiral centre each with its own chemical and biological properties. is in a critical binding area. Location in a non-critical This has led, in some cases, to marketing the separa- area implies low or no stereospecificity or selectivity in ted, therapeutically effective, enantiomer (Table 1). biological properties, ie chirality is silent. One and the An example is the exploitation of the undesirable same chiral centre may be located in a non-critical respiratory depressant in some racemic analgesic (silent) position for a particular type of receptor and narcotics. Separation of the enantiomers showed that still be critical for other receptors or enzymes involved analgesic and respiratory (antitussive) action could be in metabolic conversion. The implications of chirality parted and the individual enantiomers marketed as for various aspects of drug action (pharmacodynam- different drugs (Table 2). ics) and drug metabolism (pharmacokinetics) may thus clearly differ. This holds true also for stereo- Racemic drugs and pharmacological measurements isomers other than enantiomers, such as cis- and trans- (also called Z- and E-) isomers, compounds with a The terminology 'active' and 'inactive' enantiomers is carbon-carbon double bond (Fig 1). For reasons of misleading. The enantiomer most potent for the simplicity we will restrict ourselves here to compounds desired action is called the eutomer, and the one with- with only one chiral centre. out such action the distomer. The latter often particu- Figure 2 presents in a schematic way the distribution larly contributes to undesired actions of drugs, pesti- of our present therapeutic arsenal based on chirality. cides etc and can never be regarded as completely In natural and semisynthetic drugs, single-isomer harmless. The ratio of the activities of eutomer and products predominate; most synthetic drugs are either distomer is called the eudismic ratio. It usually differs racemic or non-chiral. This underlines the fact that for the various components of the desired and un- chirality is not a prerequisite for biological activity; desired actions generated at different receptors. The whether chirality plays a role depends on the target ratio is specific for a particular racemate in relation to molecules (receptors, enzymes etc). a particular action and is only rarely equal to 1. Racemic drugs require special consideration. For The eudismic proportion is the proportion of the con- natural products, a mixture of enantiomers is usually centrations of eutomer and distomer in plasma or the result of racemisation which may be hard to avoid. other body fluids. It is of specific significance in phar- In the case of synthetic products, the high percentage macokinetics. For the racemate itself, the eudismic of racemic drugs is largely an unhappy inheritance. proportion is 1 by definition. After absorption, stereo- The presence of 50%, 75% and sometimes even more selectivity in metabolic conversion will gradually

396 Journal of the Royal College of Physicians of London Vol. 28 No. 5 September/October 1994 Chiral cognisance

Table 1. Therapeutic effects and side-effects of the individual isomers of a racemate

Drug Eutomer Inuseas/for Distomer Effect of isomeric ballast

Levodopa /-isomer Antiparkinsonian ^-isomer Agranulocytosis Penicillamine d-isomer Antirheumatic, Wilson's disease /-isomer Neurotoxic, pyridoxine deficiency

a state is Table 2. Racemates of which both change the eudismic proportion until steady isomers are marketed as reached for each of the enantiomers involved. Strictly separate drugs speaking, no racemate exists in body fluids with the Pair of isomers Isomer exception of rapid in vivo racemisation. Whether the Effect eutomer or the distomer is eliminated, preferentially Levorphanol I ie whether the eudismic to values Analgesic proportion changes Dextrorphan d Antitussive larger or smaller than 1, can only be detected by d so-called chiral assays. Dextropropoxyphene Analgesic / The 'composition' of a racemate in body fluids is Levopropoxyphene Antitussive not only time-but often also route-dependent. Vera- pamil is an example of a drug with different eudismic intravenous A proportions in plasma after oral and simple and effective way to stop polluting the liter- ratio for the ature with administration. The eudismic (R/S) the non-science generated in the study of on atrio- negative dromotropic action of this drug racemates would be to place an obligation on authors: ventricular conduction is 10. When taken by mouth, 'The character of which are presystemic metabolic (liver or gut) elimination is composite drugs mixtures of stereoisomers must be to the higher for the eutomer (R) than for the distomer (5), brought attention of the reader. The or in a low for the prefixes (RS)- rac, resulting systemic bioavailability rac eg -propranolol, in the case of racemates, and eutomer. The eudismic proportion in plasma is 0.2 (Z/E)- or cis/trans- in the case of after oral and 0.5 after intravenous administration, ie that type of isomer, are The at equal 'racemate' plasma concentrations the obligatory. implications of the and chiral nature of the eutomer concentration is much lower after oral than composite drugs for the of the data after intravenous administration of the drug. Plasma interpretation measured and the conclusions drawn must be made concentrations of a racemate measured by non-chiral explicit'. on the sum of the An assays give information only important issue concerning therapeutic eutomer and distomer. Since the eudismic proportion racemates is: How are the effects and the side-effects is not these concentrations will not be consis- constant, distributed between the enantiomers? Three tently related to the response; in fact, pharmacokinetic possibilities exist. constants such as a racemic drug's half-life, bio- 1. The therapeutic effect is the availability, bioequivalence and other pharmacokinetic stereoselective; side- effect is non-stereoselective and thus constants derived from 'racemate' concentrations equally divid- over ed the enantiomers. The enan- based on non-chiral assays are really meaningless. therapeutic tiomer is then a and the Further difficulties arise with respect to side-effects, hybrid therapeutic margin is doubled by the isomeric ballast. protein binding, active transport, metabolic conver- eliminating 2. The effect and the sion to bioactive metabolites, etc. Millions of dollars therapeutic side-effect are stereoselective. Chances are that the have been and still are wasted on measuring such fifty/fifty side- effect can be eliminated pseudo-scientific and misleading kinetics of drugs. by removing the (non-therapeutic) isomeric ballast. 3. If the side-effect and the therapeutic effect are Racemic drugs as a source of medicinal pollution and both components of the same pharmacological pseudo-science action, enantiomeric separation works only for toxic of reasons independent actions, biochemical One the for neglecting the presence of eg lesions. isomeric ballast in has been It is patient-polluting drugs highly improbable that the isomeric ballast would the contention that clean would be difficult and be inert drugs really and totally harmless. Its absence is the to Over the 10 stereo- best expensive produce. past years guarantee in this respect. selective synthesis and enantiomer separation have Costs can now be under con- greatly improved. kept Role of the regulating authorities trol, the more so since it is realised that in the produc- tion of racemates 50% of the often base The expensive regulatory authorities have at last to materials is wasted in agreed producing risky pollutants. require explicit justification for marketing racemic

the Journal of Royal College of Physicians of London Vol. 28 No. 5 September/October 1994 E J Ariens and E W Wuis therapeutic agents. They have issued special guidelines racemic drugs: 'Contains 50% of therapeutically for chiral drugs, notably for new racemic mixtures of ineffective, presumably harmless chemical ballast'. chemicals presented as medicines; not only the chemical of these composition drugs but also the pharmacol- Further reading ogy and toxicology of the separate enantiomers are Timmermans PBMW. and attention. But a weak is that the authori- 1 Ariens EJ, Soudyn W, Stereochemistry getting point Oxford: Blackwell Scientific Publica- ties are still to assume that side-effects which biological activity of drags. willing tions, 1982:1-190. are from the desirable of the 'predictable' properties 2 Wainer IW, Drayer DE. Drug stereochemistry, analytical methods and drug may be ascribed to the eutomer; the distomer is pharmacology. New York: Marcel Dekker, 1988:1-300. then assumed to be harmless. In view of the wide 3 Brown C (ed). Chirality and drug design and synthesis. New York: Academic Press, 1990:1-240. range of side-effects and the toxicity related to bio- 4 Jamali F, Mehvar R, Pasntto FM. Enantioselective aspects of drug chemical this is an but lesions, industry-friendly action and disposition: therapeutic pitfalls. / Pharm Sci patient-unfriendly attitude. The first question the 1989;78:695-715. physician or pharmacist should ask the medical repre- 5 Evans AM. Stereoselective drug disposition: potential for misin- of data. Br Clin Pharmacol sentative salesman) is: Which of your products terpretation drug disposition / (drug 1988:26:771-80. are racemic mixtures, and how sure are you that the isomeric ballast is completely harmless? No patient wants to swallow useless chemicals even therapeutically Address for correspondence: Dr Eveline W Wilis, Department of if reassured by the health authorities. Let us at least be Clinical Pharmacy, University Hospital Nijmegen St Radboud, PO honest and announce in bold print on the package of Box 9101, 6500 HB Nijmegen, The Netherlands.