TIPS - March 1988 [103]

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. . . . Trends in V o l u m e 9, No. 3

Pl .a ical Sciences

interactions with the, ~.~,,. extracellular raatrix: a new direction for atherosclerosis?

see page 94...

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Racemates: towards a New Year

resolution? COMMON TO the programmes ,,,-,¢ ~-,o,, many national and international gather- ings of pharmacologists in recent years - whether held in Frankfurt, Florida, Syd- ney or just recently London - has been the theme of the pharmacological implica- tions of stereoisomerism. However, the London meeting* not only addressed the scientific and clinical issues of racemates and enantiomers, but for the first time some of the regulatory aspects of the issue were outlined by a speaker from the Secretariat of the Committee of Soci- ety of Medicines. This latter aspect was greatly to be ~velcomed as it was clear that industry was showing signs of unease and anxiety in the absence o. ¢ any sort of lead statement indicating how reg- ulatory authorities were going to handle the issue. Indeed one extreme and unin- formed view, occasionally encountered, is that in the future regulatory authorities would insist on the licensing of single enantiomers only and not countenance racemates. What was said at this Sympo- sium should have gone a long way to dispel such a point of view.

It is the responsibility of a regulatory body to respond to new science and the formation of a consensus opinion. The work of numerous scientists on various aspects of stereoisomerism, as expressed at various meetings, has clearly come to a conclusion that the racemate versus enan-

• Symposium on stereoisomerism, at the Winter Meeting of the British Pharmacological Society, London, UK, 6 January 1988.

(~ 1988, Elsevier Publications, Cambridge 0165 - 6147/88/$02.00

76 TIPS ~ March 1988 [Vol. 9]

tiomer debate is a significant one and that something should be done about this in regulatory terms. The important question is what should be done? This will be returned to later. Before doing this it is instructive and of interest to look into some of the twists and angles in the development of this saga. To an outsider looking in it must seem strange that we have lost sight of a phenomenon whose importance was first made appar- ent some 70 years ago by the British pharmacologist Arthur R. Cushny. He was attracted to the problem of the biological relations of the optical isomers and he demonstrated the existence of substantial differences between the pharmacological properties of both atropine [(+)-hyoscyamine] and (-)-hyoscyamine and ( - ) - and (+)-adrenaline. So much for enantiomer differences in phar- macodynamic activity: by the end of the 1930s the studies of R.T. Williams on menthol metabolism and those of Garry and Smith on mandelic acid made it clear that there can also occur pharma- cokinetic--disposifional differences between enantiomers.

During the 1950s the import- ance of stereochemical considera- tions in medicinal chemistry and drug design was consistently emphasized by Arnold Beckett and Alan Casy in their classic studies on synthetic opiate type narcotics. Indeed during this period several powerful opiate analgesics and their antagonists were developed and marketed as single enantiomers. The message of Beckett and Casy, that when dealing with a 'handed structure' such as the milieu interieur and, more specifically, 'handed' recep- tor sites one needs to give atten- tion to the three-dimensional structure of agonist and antagon- ist structures, seems to have got diluted and largely lost during the 1960s. During the 1960s there occurred a veritable explosion in medicinal chemistry with the addition to the therapeutic arma- mentarium of novel synthetic drugs almost invariably in the racemic form!

We can only surmise at why the culture was lost in terms of its significance in drug development. One reason is that the 1960s was a period of major reform in medical undergraduate cun'icula. One

consequence of this was that the new curricula with a greater emphasis on 'relevance' reduced the time given to basic sciences such as organic chemistry and stereochemistry. Indeed stereo- chemistry is now something men- tioned only when dealing with the biochemistry of amino acids and sugars. One major effect of this, as has been pointed out by Professor Ariens in his analysis of the problem, is that few teaching and reference books in pharmacology and particularly clinical pharma- cology even mention stereo- chemistry and its significance. This has had further ramifications since innumerable papers have been published dealing with the pharmacokinetics of racemic com- pounds (and therefore mixtures): the results of such studies are notoriously difficult to assess and are dismissed, by some, as 'non- sense'. The point about this of course is that, because of the culture loss, editors and referees have not been applying the cri- teria that are necessary when dealing with manuscripts on race- mic substances. We are not trying to score party points when we say that the pressure to thrust the issue of racemates versus enan- tiomers into the limelight has largely been due to medicinal chemists, pharmacists and bio- chemical pharmacologists addres- sing a somewhat sceptical clinical community who wonder what all the fuss is about.

Enantiomers, while very differ- ent in three dimensions, are very similar in the two-dirnensional world we use to communicate scientific information. Stereo~ chemists may be thought to over- state the significance of the differ- ence between enantiomers, since they are so hard to reveal. However, these differences be- come very obvious when enan- tiomers are able to interact in various ways with other chiral centres in a chiral environment. Chemical and pharmacological laboratories are generally mislead- ingly non-chiral environments, but the universe is, at its most fundamental level, handed. Dur- ing evolution, living systems have progressively become chirally enriched, and are now found to be highly handed, being built up of molecules, such as sugars and amino acids, whose stereochemis-

try is absolutely defined. It is therefore not surprising

that living organisms are able to discriminate betwee~ the ~,'¢o enant iome~ of a chiral coin- pound, and that there occur differ- ences, often very large, between the responses they evoke. This has been recognized for drugs acting through receptor mechanisms during virtually all of the history of pharmacology and, as Pfeiffer's rule states, the greater the affinity of the drug for its receptors, the greater the enantioselectivity of action. Indeed, with the present emphasis upon the development of antagonists, their greater affin- ity for receptors further enhances their stereoselectivity of action. Differences in pA2 values between enantiomers of 4 and 5 (i.e. 10 000 to 100000 fold) are common. Obviously analogous situations will operate with drugs whose activity arises from binding to enzymes or membrane structures.

In contrast, it is only recently that we have become aware of the true importance of stereochemis- try in drug disposition. In the past we lacked analytical methodology appropriate for the determination of the enantiomeric composition of chiral drugs at therapeutic con- centrations in biological milieux. Technical developments in the past five or so years now permit us to determine the concentra- tions of individual enantiomers, and the application of these novel methods now enables us to dis- cern stereochemical influences in the processes of absorption, dis- tribution, protein binding, meta- bolism and elimination. These processes are in general relatively non-selective, with the result that their ability to discriminate between enantiomers is corres- pondingly reduced. Overall, it is unusual to find pharmacokinetic differences of more than fiv~-f~!d between enantiomers, but it must be remembered that this may obscure much greater variability occurring with the individual pro- cesses contributing to drug hand- ling. The significani enantioselec- tivity of certain of the drug meta- bolizing enzymes, both in terms of drug substrate and of product metabolite, is now well recog- nized, and again is most evident with high affinity substrates. The active transport systems of the renal tubules may also show con-

TIPS - March 1988 [Vol. 9] 77

siderable enantioselectivity.

Responses of the regulatory authorities

The regulatory-n~thorities are beginning to respond to the scien- tific and clinical maelstrom con- cerning the issue of racemates and enantiomers. In the United States the Food and Drug Administra- tion has both an ongoing intra- mural discussion and an extra- mural debate with industry which is likely to lead ~o the promulga- tion of guidelii~es. Matters are further advanced within the EEC, where at present the Committee for Proprietory Medicinal Pro- ducts is considering a draft guide- line statement on isomerism for inclusion in its 'Notice to Appli- cants'. If adopted, as looks likely, new submissions for drugs with chiral centres w~.'U have to provide information inter alia on the fol- lowing points: isomer ratio and batch to batch consistency; a dis- cussion of the toxicologic~ and pharmacological properties of the isomers, enantiomer-specific meta- bolism and kinetics and the extra- polation of preclinical data (parti- cularly if species differences occur in the handling of stereoisomers); and a discussion of possible clini- cal problems that may arise in relation to stereoisomers.

In Japan the health authorities, in meetings with the pharma- ceutical industry, have explained their requirements in the context of the registration of a racemic mixture or optical isomer. Basic- ally, for a racemic mixture, infor- mation will be required on the toxicity pharmacology (efficacy and general) and the disposition of each isomer. Also when the active component is either of the two isomers, information will be required on the extent of intercon- version of the two isomeric forms. Presumably, this will apply in the main to anti-inflammatory pros- taglandin synthetase inhibitors, based upon chiral arylpropionic acid structures known to undergo the generic process of chiral inver- sion. Lastly, information will be required on isomer purity: if one of the isomers constitutes a major 'impurity' then this will have to be fully studied in terms of toxi- city, pharmacology and dispos~(- tion.

What all these new guideline requirements add up to is of

course the aecessity to have a much better scientific under- standing of a drug product, p~,rfi- cularly if it is being presented in a racemic form.

What can be done in the future Quite apart from specific reg-

ulatory guideline requirements, a number of issues need to be addressed as part of a general response. Firstly, medical under- graduate courses in pharmacology and clinical pharmacology should contain sufficient reference to stereochemistry and its signifi- cance so that physicians under- stand the problem. It is hoped too that authors and editors, when revising teaching texts in pharma- cology, will remedy any omission and include a section on stereo- chemistry. In the same vein edi~ tors of journals should draw up an editorial policy with respect to the specific issues surrounding race- mates and enantiomeric sub-

As far as the industry and the development of racemates or enantiomers is concerned, it is our view that it would be a mistake to have rigid guidelines. When deal- ing with a racemic compound it is important that the company shows that it understands the science of the mixture in terms of understanding the relative phar- macological and toxic properties of each component and any interactive potential. Decisions on whether or not the racemate or enantiomer is developed for mar- keting should in our view be taken on a case-by-case basis. There will be cases where the therapeutic ratio is enhanced by the use of a single enantiomer and others where it will not make a lot of difference. Moreover, other fac- tors have to be taken into account in the decision-making process inc!uding feasibility and cost of stereospecific enantiomer syn- thesis or separation and quality control of isomeric purity. All in all, this probably argues Lot some sort of 'decision tree' approach t~ the issue, incorporating factors such as pharmacological and tox- icological properties of the enan- tiomers, pharmacokinetic prop- erties, interactive potential, feasi- bility and cost of production, quality control criteria and 'mar- keting edge'.

Cjome may find all this some-

what daunting. Nevertheless, the re-realization of the impoff~nce of stereochemistry in pharmacology, in our opinion, has an important contribution to make to the development and use of safer and more effective medicines. How- ever, one well-known medicinal chemist was heard to exclaim at the end of the Symposium, 'I shall now ban the synthesis oL an chiral compounds in my laboratory for the future!'. ROS~.RT L. SMITH

AND JOHN CALDWELL Department of Pharmacology & Toxicology, St Mary's Hospital Medical School, London W2, UK. Further reading TiPS chirality series (1986) Trends Pharma- col. Sci. 7, 20--23, 60-64, 112-116, 155--158, 200--205 and 227-230.

~ I I I / ' i ' t l ' i ' i i / i " I I I I I I I l l i | t I I I I I ! I i l l I ~ I I I I l _ l_J ! I I I I

l l l K ' l . . ! i ,1111/ i l111111~kkr I i I I I ! i = P r - r l - r ~ ' P t ~ j ' r A i I i I i I I l l I I i i I i ! L,~ ~ I | ! I I I ! l l ~ . .g l f3" Ik l !e i I ~ r - I i i i ! i i l l J i w ~ l r u l - . r t t I I i I I j i i i i FRANCE: On the advice of the Commission Nationale de Pharma- covigilance, the Ministry of Health has extended by one year the temporary withdrawal from the market of isoxicam (Vectren®), during international inquiries which now progress in some countries, x.j.x.

[] [] []

FRANCE: On the advice of the Commission Nationale de Pharma- covigilance, the Ministry of Health has recommended extension of contraceptive measures from 12 to 24 months after the end of treat- ment with e t r e f i n a t e (Tigason®).

R.J.R. [] [] []

AUSTRIA: In accordance with new regulations from the Ministry of Health, all phenacefin-contain- ing drugs have been withdrawn from the market. O.K.

[3 [] [] JAPAN: Following repeated re- ports of severe lung-related side- effects, the Adverse Effects Investi- gation Committee of the Central l-"barmaceutical Affairs Council has recommended revision of warnings ~nd precautions in the labelling of bleomycin and ~eplo- mycin and dissemination of safety information to doctors. Information on Adverse Reactions to Drugs, 86, August 1987. I.s.