PHARMACOCHEMISTRY LIBRARY
`
`Editors: W.Th. Nauta and R.F. Rekker
`
`
`
`Volume 4
`
`STRATEGY IN DRUG
`RESEARCH
`
`Proceedings of the second |UPAC—|UPHAR Symposium held in
`Noordwijkerhout (The Netherlands), August 25-28, 1981
`
`Edited by
`
`J. A. KEVERLING BUISMAN
`
`c/0 Duphar BV, Weesp, The Netherlands
`
`
`
`ELSEVIER SCIENTIFIC PUBLISHING COMPANY
`
`Amsterdam — Oxford — New York
`
`1982
`
`MYLAN - EXHIBIT 1023
`
`MYLAN - EXHIBIT 1023
`
`

`

`P.O. Box 211, 1000 AE Amsterdam, The Netherlands
`
`Distributors for the United States and Canada:
`
`ELSEVIER SCIENCE PUBLISHING COMPANY INC.
`52, Vanderbilt Avenue
`New York, NY 10017
`
`Cover design by Dr. C. van der Stelt
`
`Library of Congress Cataloging in Publication Data
`Main entry under title:
`
`Strategy in drug research.
`
`(Pharmacochemistry library ; V. M)
`Organized by the Medicinal Chemistry Division of the
`Royal Netherlands Chemical Society under the sponsorship
`of the International Union of Pure and Applied Chemistry,
`Commission on Medicinal Chemistry, and others.
`Includes index.
`'
`2. Structure
`l. Pharmaceutical research-—Congresses.
`—activity relatio ship (Pharmacology)
`1. Keverling
`Buisman, J. A.
`(Jan Anne)
`II. International Union of
`Pure and Applied Chemistry. Commission on Medicinal
`Chemistry.
`III. International Union of Pharmacology.
`IV. Series.
`[DNLM: l. Pharmacology——Congresses.
`2. Research——Methods—-Congresses. W1 PH272L V.H / QV 205
`I92 1981s]
`,
`RSl22.S77
`6l5’.l'072
`ISBN 0-huh-u2o53—3 (v. 4)
`
`8i—i9u76
`AACRQ
`
`ISBN 0444-42053-3 (Vol. 4)
`ISBN 0-444-41564—5 (Series)
`
`© Elsevier Scientific Publishing Company, 1982
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or
`transmitted in any form or by any means, electronic, mechanical, photocopying, recording or other-
`wise, without the prior written permission of the publisher, Elsevier Scientific Publishing Company,
`P.O.Box 330,1000 AH Amsterdam, The Netherlands
`
`Printed in The Netherlands
`
`

`

`J .A. Keverling Buisman (Editor), Strategy in Drug Research
`© 1982 Elsevier Scientific Publishing Company, Amsterdam — Printed in The Netherlands
`
`165
`
`OPTIMALIZATION OF PHARMACOKINETICS - AN ESSENTIAL ASPECT OF DRUG DEVELOPMENT -
`
`BY "METABOLIC STABILIZATION"
`
`E,J_ ARIENS
`
`and A.M. SIMONIS
`
`Institute of Pharmacology and Toxicology, University of Nijmegen,
`
`the Netherlands
`
`1)
`
`INTRODUCTION
`
`Generally speaking,
`
`the chemical properties and hence the chemical structure of
`
`a compound definitely determine the way in which it participates in the Various
`
`part—processes involved in biological action. A structure-action relationship
`(SAR),
`therefore, has to be a fundamental characteristic of bioactive agents. The
`
`apparent absence of such a relationship can only be due to deficient methods of
`investigation and to the multiplicity and complexity of the process as a whole.
`
`Although the various part—processes are biochemical and physicochemical in nature,
`
`they differ greatly. Totally different SAR patterns may be expected for, for
`instance,
`the rate of absorption,
`the mode of distribution,
`the renal excretion,
`
`to
`the various types of metabolic conversion, and the capacity of the agent
`activate the molecular sites of action (the receptors) in the target tissue - the
`
`structure-action relationship in a strict sense. Absorption, distribution and
`
`excretion, which are mainly based on passive diffusion processes, will largely
`
`depend on partition coefficients. Metabolic conversion will depend mainly on the
`presence in the molecule of particular groups that are open to attack by enzymes.
`
`These groups as a rule have little or nothing to do with the chemical characteristics
`which are essential for the induction of the effect. Whether an agent is hydrolysed
`
`by esterases, for instance, depends mainly on the presence of a suitable ester
`group in the molecule. The ester group, however, has little or nothing to do with
`the question whether the agent has a curariform, an anticholinergic, a local
`anesthetic action,
`is an insecticide, a herbicide, a plasticizer, or some toxon.
`
`Whether an agent is capable of inducing a particular type of biological effect
`
`is usually dependent on various specific chemical characteristics in the molecule.
`
`SAR will emerge most clearly if it is studied for particular part—processes such
`as those involved in absorption, distribution or excretion, where passage of
`
`membranes is essential,
`
`those involved in drug metabolism, where SAR will depend
`
`the induction of
`on the particular enzyme, and SAR for the final step of action,
`the effect.
`In a comparison of the quantitative dose—effect relationship for a
`
`References p. 1 78
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`of SAR for the various part—processes.
`
`2) THE MAIN PHASES IN BIOLOGICAL ACTION
`
`The complex of processes involved in biological action can be split up in three
`{ll
`1)
`(re
`1, 2).
`phases (Fig.
`
`I Pharmaceutical phase
`
`II Pharmacokinetic phase
`
`III Pharmacodymiinic phase
`
` disinlcgralion of drug available
`
`Dose
`dusagg form
`for absorption
`j’ ‘
`-
`dissolution of
`pliarmaceuilcal
`active substance
`availability
`
`absorption
`distribution
`-
`metabolism
`excretion
`
`drug available
`for action
`biological
`availability
`
`in target tissue
`
`di,ug_i,ecepmr
`intemciio
`n
`
`i
`—> liiflcvl
`
`I.
`
`The pharmaceutical phase
`
`This phase comprises the processes that are determinant for the efficacy of the
`application. Here the disintegration of the dosage form,
`tablets, capsules, etc.,
`
`in such a way that the active agent becomes available in a molecular dispersed form
`suitable for absorption, and avoidance of chemical or enzymatic activation of the
`active agent before absorption, e.g.
`in the intestinal tract, count.
`In general,
`
`for the absorption - which implies passage of biological membranes — the lipid/water
`
`solubility and therewith the partition coefficient is determinant. For weak bases
`
`and acids also the degree of ionization and therewith the pKA of the compound and
`the pH at the site of absorption count. The fraction of the dose available for
`
`absorption is indicated as the "pharmaceutical availability". The time course of
`the events has to be taken into account,
`too, and results in the "pharmaceutical
`
`availability profile".
`
`II. The pharmacokinetic phase
`
`This phase comprises the processes involved in absorption, distribution, excretion
`and metabolic conversion of the agent after absorption. The fraction of the dose
`
`that reaches the general circulation is indicated as the "biological
`
`(systemic)
`
`availability”. Also here the time course represented in the "biological availability
`
`profile” is of particular significance. The concentration of the active agent in
`
`the target tissue as a function of time is represented by the "pharmacological
`
`In the pharmacokinetic phase, besides the lipid/water
`availability profile”.
`solubility and degree of ionization of the agent, particularly its sensitivity to
`
`various enzymes counts. The presence in the molecule of vulnerable moieties accessible
`to enzymatic attack plays a predominant role. In this respect,
`like in the case of
`active, carrier-related transport,
`the charge distribution of the agent and its
`
`steric properties are determinant factors. The metabolic conversion of the
`
`agent applied may result in its bioinactivation (biodetoxification) or bioactivation
`
`

`

`167
`
`(biotoxification).
`
`The involvement of Various metabolites greatly complicates pharmacokinetics.
`Metabolic conversion usually increases hydrophilicity thus facilitating renal ex-
`cretion.
`
`III. The pharmacodynamic phase
`This phase comprises the processes involved in the interaction between the bio-
`active compounds and their molecular sites of action, receptors, enzymes, etc.
`Pharmacon—receptor interaction results in the induction of a stimulus which initiates
`a sequence of biochemical and biophysical events which finally lead to the effect
`observed.
`
`3) PHARMACON MTABOLISM, A NATURAL DEFENCE AGAINST INTRUSION OF CHEMICALS (XENO-
`BIOTICS),
`INCLUDING DRUGS
`Although one might get
`the impression that the toxicological risks involved in
`the exposure to chemicals,
`including drugs, are generated by the evolvement of
`chemical and pharmaceutical industries and thus are of recent origin,
`this is
`definitely not
`the case. Already since the very beginning of evolution living systems
`have been exposed to chemicals. This especially holds true for the heterotrophic
`organisms (in general, animal life) which are to a large extent dependent on the
`consumption of autotrophic organisms (mainly plant material) and are exposed,
`therefore,
`to a great variety of potentially toxic chemicals of plant origin. These
`plant products are xenobiotic to the animal concerned. The term "biogenic xeno-
`biotics” is appropriate here.
`the problems were relatively small,
`As
`long as life was limited to the oceans,
`since there was a tremendous water compartment available for the disposal of un-
`desired body-foreign chemicals, even if these were rather lipid-soluble. The
`"affinity" thereof for the relatively lipophilic biomass was
`counterbalanced by
`the tremendous volume of the disposal compartment. Photodegradation and oxidation
`in the surface layers of the waters largely took care of chemical degradation. By
`the time animal life switched from water to land,
`this opportunity got lost. Water
`became relatively scarce and only a small volume became available for disposal
`(for man about
`1 liter a day). This increased the danger of accumulation of lipo-
`philic, poorly water—soluble agents in the biomass. In the line of evolution an
`answer was found in the development of enzyme systems which take care of the con-
`version of relatively lipophilic compounds into highly water soluble end—products
`suitable for renal excretion (table 1). This conversion occurs in two steps: a first
`predominantly oxidative step and a second predominantly conjugational step (Fig. 2).
`Simultaneously, a strong increase in the concentration of plasma albumin took place
`(table 1),
`important for osmotic regulation but serving as well as a temporary
`sink, a kind of parking lot, for lipophilic xenobiotics. Such agents would easily
`pass the various membranes in the body and so enter tissues and cells where damage
`
`References p. 1 78
`
`

`

`Speciex
`
`man
`dog
`turtle
`crocodile
`frog
`skate
`menhaden
`goosefish
`
`Plasma protein
`"/D
`6.5
`6.1-6.7
`4.8
`3.69
`1.5-4.3
`2.4-3.1
`0.72—2.9
`1.4-2.2
`
`Oxidurfve
`N-demethylalion ‘
`19
`t 2
`15
`4; 2
`26
`t 8
`4
`1 0.6
`1.6
`: 0.45
`1.1
`t 0.30
`0.71 3 0.28
`0.86 x: 0.23
`
`Phenol
`glucuronidariond
`21
`1 3
`46
`1 13
`85
`1 22
`8.9 J;
`2.3
`1.26 : 0.47
`1.72 1 0.25
`1.9 1 0.33
`2.68 1 0.65
`
`Specie;
`
`mouse
`rat
`pigeon
`lizard
`frog
`trout
`goldcnorfe
`carp
`
`Curnoles formaldehyde formed per gram fresh liver tissue/hour.
`d
`.
`.
`.
`.
`.
`umoles p-nitrophenol glucuronidation per gram fresh liver tissue/hour.
`
`Note the increases at the switch from water to land animals.
`
`PH A R M ACA
`
`hydrap/7//fc
`
`polar
`
`//‘pap/7///Z‘
`
`BUFFERSYSTEM
`
`INTRAVASC. CARR I ER
`albumin binding
`
`
`
`
`
`a7/ky/.9t'i/1g‘
`/1/3'/1/y //'po;I/7i//"C
`agfis
`metabolically stable
`CHEMICAL
`PHY5|CAL
`5EQUELf>Tl2A'f'IQ_N
`SEQUESTRATION
`I
`caudanfheouebcndmg
`accumu|al:ionmFat
`i
`PHASE 1
`.
`_
`
`“(“‘’‘’‘’/7_’/"’
`(bio-activation or bio~lnactivafior1)
`
`. 5/kV/‘I'll;
`oxidation , reduction
`/ntermid/ates
`hydrolysis
`
`
`
`
`
`
`I E
`
`i
`_i
`
`reabso rption
`
`
`
`PHASE I!
`( b.iqh-inactivalriorl )
`conjugation
`
`extracellular mobilization
`blood circulation
`
`ultra~
`
`Filtration
`
`
`
`
`
`//‘pop/1///c
`/vydz-op/vi/ic
`l
`l
`_
`urn-Ie
`
`biliary
`active
`excretion
`
`reabeorption
`
`hydrol seal
`
`conjugates
`5:1
`intracellular
`processes
`
`Faeces
`
`Fig. 2. Schematic representation of the main steps in drug metabolism and
`elimination.
`
`

`

`169
`
`might be done. Binding to albumin implies lowering of the free concentration in
`plasma and therewith lowering of
`the effective concentration to which cells and
`
`tissues are exposed. The agents involved are temporarily stored on the albumin in
`
`the circulation, where they are available for the enzymes, particularly in the liver,
`
`that especially take care of biochemical conversion to products that are suitable
`for renal excretion (ref. 3).
`
`industry came to development,
`In short, by the time chemical and pharmaceutical
`animal and man were more or less prepared for dealing with - in fact for defence
`
`against - exposure to the products of these industries, "synthetic xenobiotics",
`including drugs,
`thanks to their experience with ”biogenic xenobiotics".
`
`4) DRUG METABOLISM " DETOXIFICATION AND TOXIFICATION
`
`In the early days of studies on this subject, drug metabolism was put more or less
`
`synonymous with detoxification as indicated, for instance, by the classic book
`
`entitled "Detoxication Mechanisms" by R.T. Williams, 1959 (ref. 4). In the case
`the metabolic elimination of xenobiotics concerns the application of drugs as
`therapeutics,
`the action is considered, at least by the prescribing physician, as
`
`desirable, although some components in the action still may count as undesirable, i.e.
`
`as side—effects.
`be distinguished:
`1)
`the generation of toxic metabolites, still xenobiotic in nature, biotoxification;
`
`In fact in drug metabolism two classes of undesirable aspects can
`
`2)
`
`the untimely elimination of the drug and complication of pharmacokinetics with
`
`as a consequence blurring of the dose-effect relationship due to drug metabolism.
`
`5) BIOTOXIFICATION
`
`Drug metabolites may be biologically active and in some cases are fully responsible
`
`for the action of the drug, which then in fact must be considered as a prodrug.
`
`With regard to the bioactive metabolites, distinctions can be made between:
`a) stable metabolites, active in a pharmacological sense, producing effects mostly
`
`related to that of the mother compound. This type of bioactivation which depending
`
`on the circumstances may be considered positive or negative will not be discussed
`in further detail here.
`
`b) Chemically highly reactive, electrophilic, biologically alkylating inter-
`
`mediate products with a very short half—life time,
`
`formed in the course of
`
`the metabolic conversion - particularly oxidation, but also conjugation reactions.
`
`These intermediates act under covalent binding with nucleophilic groups on biological
`
`macromolecules such as nucleic acids and proteins. The resulting "chemical lesions”
`
`may have serious consequences such as:
`
`lesions in chromosomal DNA
`involving chemical
`a) carcinogenesis,
`b) mutagenesis, also involving chemical
`lesions in chromosomal DNA
`
`c) possibly accelerated aging, caused by an increase in the error frequency in-
`
`References p. 1 78
`
`
`
`
`
`II ,-.71:
`
`I I I I’
`
`I
`
`'I
`
`

`

`teratogenesis, caused by disturbed cell proliferation due to chemical
`d)
`during embryogenesis,
`
`lesions
`
`e) allergic sensitization, due to chemical
`act as allergens,
`
`lesions in proteins that cause them to
`
`f) cell degeneration and necrosis, due to chemical damage to the membranes of
`
`lysosomes or to essential enzymes,
`
`involving formation of reactive products by radiation of
`g) photosensitization,
`the drug or its metabolite(s),
`thus causing local chemical lesions, or formation of
`allergens.
`
`As a matter of fact,
`
`toxic effects such as the ones just mentioned may also be
`
`induced by directly alkylating agents, such as
`
`some cytostatics used in the chemo-
`
`therapy of cancer. Particularly troublesome with regard to the carcinogenesis and
`mutagenesis is the latency,
`the long lag-time between exposure to the agent and
`
`the appearance of the effect. This is partly due to the irreversible nature of the
`chemical
`lesions, which implies an accumulation of the effect. Like in the case
`
`in fact each dose, how small it may be, counts
`of exposure to ionizing radiation,
`and contributes to the effect. The total lifetime exposure constitutes the dose.
`
`Further, especially for lesions in chromosomal DNA, "syncarcinogenesis" due to
`various agents has to be taken into account. The chemical
`lesions in proteins are
`reversible to a certain extent on the basis of de novo synthesis of proteins. If the
`
`damage is limited, it may be largely reversible. This is not
`
`the case for protein
`
`damage resulting in allergic sensitization where the immunological memory of the
`
`lymphocytes is involved.
`
`In the case of damage to DNA,
`
`to a certain extent,
`
`especially short term, repair mechanisms may eliminate part of the chemical lesions.
`
`lesions
`Metabolic systems protecting against biochemical
`In the line of evolution, nature not only developed biochemical clearance systems
`
`the risks thereof, namely those in-
`for xenobiotics, but also systems to control
`volved in the formation of reactive intermediate metabolites. The major protecting
`
`the glutathione transferase system, coupling glutathione to the
`systems are:
`chemically reactive, biologically alkylating metabolic intermediate, under the
`formation of conjugation products that appear in the urine as water soluble mercap-
`turic acid derivatives (Fig. 3) and methylthiolation which implies the coupling of
`
`(-SCH3) group to the chemically reactive, electrophilic group in the
`a methylthio
`alkylating metabolic intermediate, which thus is detoxicated. Further there is the
`
`epoxide hydratase system taking care of the hydrolysis of alkylating epoxides under
`the formation of diols which appear in the urine mostly as water-soluble phenol
`
`sulphate conjugates (Fig. 3) (ref.
`
`1, 2, 5, 6).
`
`Conjugation products such as those formed by acetylation or sulphate conjugation J5
`
`

`

`BIOCHEMICAL TOXOGENES 15
`
`171
`
`PFBEOXOU ----——————————————————§§
`
`. —————>
`oxidative
`conversion
`
`_
`sulfate etc
`conjugation
`
`-
`
`alternative, non-risky
`hydrolytic, oxidative and conjugational
`me tabo Zic pathways
`
`ultimate toxon
`electrophilic
`biologically alkylating
`
`critical nucleophiles
`DNA, proteins, etc.
`_
`1’
`_
`chemical Zesion
`carcinogenesis
`mutagenesis
`allergic sensitization
`teratogenesis
`cell damage
`cell necrosis
`
`protective systems
`
`glutathion transferase
`
`eporide hydratase
`
`phenols
`i
`sulfate conjugation
`l
`organic
`sulfates
`
`mercapturic acid
`derivatives
`
`test
`
`mercapto
`
`Fig. 3.
`
`a rule are considered as harmless final detoxification products. However, although ex-
`
`ceptionally, also such conjugation products, may be chemically reactive, biological-
`ly alkylating, and thus toxic. Also here the glutathione transferase system has a
`protective function.
`
`Oxidation products formed in the course of drug metabolism may also lead to per-
`
`oxides and oxidation products with a toxic character with regard to redox systems.
`
`An example of the damage caused is the formation of methemoglobin from hemoglobin.
`
`The latter type of action is well known for aniline derivatives. Again, glutathione
`
`has a protecting action since it contributes to the regeneration of hemoglobin
`from methemoglobin.
`
`Early detection of biotoxification
`
`It will be clear from the foregoing that considerations on drug metabolism and
`its consequences such as biotoxification are essential already in an early phase,
`if possible on the drawing table, of drug design. Reasoning
`on the relationship
`between chemical structure and action in this respect implies recognition in the
`
`References p. 1 78
`
`

`

`N
`
`'
`
`K
`V
`
`V
`
`structures of chemical groups potentially open to metabolic conversion. One has
`to differentiate between moieties leading to non-risky conversion - being
`
`the
`particularly significant for the bioavailability and duration of action,i.e.
`pharmacokinetics — and to risky conversion via reactive, alkylating intermediates
`
`particularly significant for toxicity. Moieties determining the lipophilicity of
`the compound are especially important
`in absorption, distribution and excretion and
`thus for pharmacokinetics (ref.
`1, 2).
`Remarkably, up to now, very little attention has been paid to the relationship
`between chemical structure and pharmacon metabolism. There is no doubt
`that such a
`relationship exists and even that in many cases, for instance in the case of
`
`the relationships are relatively clear and simple.
`particular enzymatic conversion,
`In vivo, however, often multiple metabolic pathways and a sequence of different
`
`metabolic steps are involved. Avoidance in the chemical structure of moieties
`
`potentially involved in biotoxification is advisable. Once compounds have been
`
`in order
`synthesized, a testing on mutagenic and carcinogenic action is advisable,
`to select or at least incorporate in the groups of compounds to be studied,
`the
`
`agents with a reduced risk with respect to the causation of chemical lesions. The
`use of
`the Ames-test, or better a properly chosen set of such in vitro tests,
`
`gives a reasonable indication of the risk for a mutagenic and carcinogenic action
`(ref. 7, 8, 9).By the way, one has to be well aware that even,although there is not
`a 100% correlation between mutagenic action as detected by such in vitro tests and
`
`the carcinogenic action in vivo, mutagenesis as such - for which the bill will be
`
`paid by future generations - , should be taken at least as serious as carcinogenesis.
`A covalent binding of
`the toxon to biopolymers has as a consequence that the
`toxon cannot be extracted from the tissues anymore with hydrophilic or lipophilic.
`solvents. A chemical sequestration is involved,
`to be distinguished from a physical
`
`sequestration where the compound, due to its metabolic stability combined with
`high lipophilicity,
`is kept back in the organism, predominantly by dissolution in
`the body fat.
`In balance studies, relating the dose to the quantity of the agent
`excreted,
`the fraction missing in that balance is important, even if it may be
`
`small, especially if chemical sequestration is involved (ref. 10).
`The final inevitable step in the testing of a new drug, before its release for
`
`is the study of its carcinogenic potential in animal species. This
`practical use,
`still does not present a 1002 safeguarding. Even after the agent has been released
`
`for application to the patient it has to be monitored in a toxicological sense. In-
`troduction in a number of steps, comprising larger and larger groups of individuals,
`
`for drugs widely used for minor ailments numbering many thousands of individuals,
`is advisable.
`
`

`

`173
`
`6) BLURRING OF PHARMACOKINETICS AND THUS OF THE DOSE-EFFECT RELATIONSHIP BY DRUG
`METABOLISM
`
`Therapeuticals usually are metabolized and eliminated at the time that the action
`
`thus sequential dosages have to be supplied. This in fact means a
`is still wanted;
`drug waste. Also other aspects of drug metabolism count as negative, e.g.
`the first-
`
`pass losses, due to metabolic conversion in the intestinal wall and the liver,
`
`the
`
`patient-to-patient and intra—patient variations in metabolic capacity with as a
`
`result a highly variable bioavailability, and the drug interactions related to drug
`
`metabolism. A highly variable relationship between dose and plasma level due to
`drug metabolism makes expensive therapeutic monitoring on basis of plasma level
`
`measurements,especially of drugs with a small
`
`therapeutic margin,necessary. Species
`
`differences, mostly related to differences in drug metabolism make extrapolation of
`animal data to the human situation difficult. An answer
`to the problems inherent in
`
`drug metabolism may be the development of drugs resisting drug metabolism, metabolic
`
`stabilization (ref. 1, 2, 1]).
`
`If short or ultrashort action is required or at local application, systemic action
`
`has to be avoided,
`
`introduction of suitable, safe, vulnerable moieties may be re-
`
`quired. The same holds true in the case that the prodrug principle is to be applied.
`In general, however, avoidance of drug metabolism or reduction of it to the possible
`minimum will be advantageous.
`
`For metabolically stable agents pharmacokinetics (absorption, distribution and
`
`excretion) are mainly determined by the balance between lipid and water solubility
`
`as expressed by the partition coefficient which in its turn is related to the pKA-
`value. An exception has to be made for active transport processes. A modulation of
`
`pharmacokinetics on the basis of adaptation in the partition coefficient will
`
`usually be much simpler than adaptation in the metabolic pathways and the rates of
`conversion. Often various metabolic pathways and a sequence of different metabolic
`
`conversions are involved in the processing of one drug.
`
`with regard to metabolic stabilization two aspects have to be taken into account:
`
`1) Metabolic stabilization in general, predominantly aimed at the simplification
`and control of pharmacokinetics.
`In this case a reduction of the fraction of the
`dose metabolized counts.
`
`2) Metabolic stabilization, particularly concerned with those moieties in the
`
`molecule that can be converted to electrophilic, alkylating groups. The aim is to
`
`In this case a reduction in the absolute quantity of
`control biotoxification.
`reactive intermediates counts.
`
`7) METABOLIC STABILIZATION TO CONTROL PHARMACOKINETICS
`
`Metabolic stabilization implies a longer half-life time and therewith less drug
`waste,
`less exposure to unnecessary quantities of the drug in repeated application,
`
`and simpler dosage regimens and therewith a better patient compliance.
`
`References p. 1 78
`
`

`

`l
`l
`l
`
`.
`
`1
`
`Metabolic stabilization contributes to a reduction in drug interactions which in
`many cases are generated on the drug metabolic level.
`Metabolic stabilization reduces the patient-to-patient and the intra—patient
`variability in the relationship between dose and effect, since this variability is
`largely based on differences and variations in the drug metabolic capacity.
`Metabolic stabilization will reduce the variability in the relationship between
`
`dose and plasma concentration. This will reduce or eliminate the need for expensive
`therapeutic monitoring via plasma drug concentration measurements for drugs with a
`relatively small therapeutic margin. The uncertainty in the dose—effect relationship
`which enforces plasma level monitoring is largely related to the variability in
`
`drug metabolism. Therapeutics that require therapeutic monitoring should be replaced
`as soon as possible by analogously acting new drugs which are pharmacokinetically
`better controlled, an aim which may be realized by metabolic stabilization. Such
`
`new drugs definitely cannot be regarded as ”me—too" drugs, but in fact are badly
`needed revisions in the therapeutic arsenal
`(ref. 12, 13, 14).
`Metabolic stabilization implies a reduction in species differences which are
`
`largely related to species differences in metabolic capacities. It will make the
`now highly uncertain transfer of animal data to man more reliable.
`Metabolic stabilization will greatly reduce the number and significance of
`
`possibly active metabolites, which implies a fargoing reduction of elaborate and
`expensive studies on drug metabolites on both the preclinical and clinical level.
`Metabolic stabilization will reduce the chance that the drug applied in fact is
`
`a prodrug or the situation that, besides the active agent applied, a number of more
`or less similarly active, but pharmacokinetically different metabolites complicate
`the picture. These situations which occur incidentally should in no way be regarded
`as advantageous.
`In the given circumstances it is advisable to consider (one of)
`the active metabolite(s) as a potential drug. Clearcut examples of this situation
`
`are found among the benzodiazepines (table 2). Various benzodiazepines on the
`market are in fact benzodiazepine metabolites. The use of the therapeutically
`active metabolites as such, especially the ones in the most advanced oxidized state,
`
`will automatically reduce the impact of metabolic conversion and thus reduce both
`the metabolic toxicological risks and the complexity of pharmacokinetics. If so
`
`to enhance absorption
`the metabolite can be presented as a prodrug - e.g.
`required ,
`of the usually more hydrophilic metabolite. This has as a matter of fact to be
`based on a safe metabolic handle for bioactivation. As such,hydrolytic cleavage is
`
`to be preferred,but also oxidation of a saturated alkyl side-chain may be considered.
`
`Unsaturated alkyl side-chains may lead to risky epoxides. Similar reasonings hold
`true if a vulnerable moiety has to be introduced into the molecule in order to
`
`obtain an ultrashort or short action or to avoid systemic action after local
`
`application.
`
`

`

`TABLE 2
`
`Chlordiazepoxide
`(7-28)
`
`demoxazepam
`(14-95)
`
`medazepam
`(2-3)
`
`diazepam
`(20-50)
`
`nordazepam
`
`,——————/)'(42_96)
`
`prazepam
`(43-78)
`
`clorazepate
`(?)
`
`175
`
`camazepam
`(15-2])
`
`temazepam
`
`(3-6)
`
`oxazepam
`(3-6)
`
`Flow scheme of benzodiazepine metabolism.
`
`All substances (half—life in hours) are in use as drugs.
`
`8) METABOLIC STABILIZATION AND CONTROL OF BIOTOXIFICATION
`
`The aim is a reduction in the absolute quantity of reactive intermediates formed.
`There are two approaches here:
`
`a) reduction in the dose of the drug required;
`b) metabolic stabilization.
`
`A reduction in the quantity of reactive, potentially carcinogenic, mutagenic, etc.
`intermediate products is to a certain extent a natural consequence of the develop-
`ment of highly potent agents. Only low dosages are required then, which implies the
`reduction of the quantity of metabolites anyway and therewith a reduction in the
`risk of induction of chemical lesions.
`
`An increase in potency, as far as related to the process in the pharmacodynamic
`phase - that is to the induction of
`the effect on specific sites of action, and not
`to, for instance,reduction in first pass loss - implies that lower plasma and tissue
`concentrations are needed for the induction of the effect desired. If the therapeutic
`effect and side-effect are induced on different target molecules (receptors, enzymes,
`etc.), an increase in the affinity to the sites involved in the therapeutic action
`only under particular circumstances will go hand in hand with a comparable increase
`in the affinity to the sites on which the side-effects are induced. An exception
`has to be made for those cases in which the higher therapeutic potency is related to
`accumulation of the agent
`in a phase (e.g. a lipophilic phase),
`in which both the
`
`sites for therapeutic effect and side-effect are located.
`
`In those cases that the
`
`increase in therapeutic potency is related to a higher degree of complementarity
`of the active agent
`to the molecular sites for therapeutic action, as a rule,
`this
`
`References p. 178
`
`

`

`lowering of the dose required also implies a smaller metabolic turnover and thus a
`reduction in the quantity of potentially toxic reactive intermediate products.
`Metabolic stabilization aimed at a control of pharmacokinetics also implies a
`reduction of the dose required and therewith a reduction in the risky metabolic
`turnover as well as a reduction in the formation of metabolic products causing
`pharmacological side—effects. If stabilization of risky metabolic handles, chemical
`groups open to conversion to electrophilic, alkylating moieties,
`is involved, bio-
`toxification is brought under control even more effectively. An alternative to
`metabolic stabilization of risky metabolic handles,
`is introduction into the
`molecule of safe metabolic handles offering a preferred alternative route of con-
`version. An example is toluene as compared to benzene (see fig. 4).
`branzh.
`liver
`kidney
`bone marrow
`lung 9.,-,||b|udd,,,
`kidney
`
` liver
`
`inlesiinul conlems inlesnnui (unlc-n|5
`
`
`xesfide
`
`kxdney
`
`a
`
`i
`
`b
`
`Fig. 4 a-b. Autoradiograms of mice 1 h after inhalation for 10 minutes of 5 pl
`14C-benzene (a) and 10 ul 14C—toluene (b). Preparation: dried and evaporated (upper),
`additionally extracted (lower). Note: benzene metabolites are irreversibly bound
`in kidney cortex and liver (a); all toluene metabolites are completely extractable (b)
`After Bergman (ref.10).
`
`The oxidative attack on the benzene ring leads to the formation of an epoxide as
`toxic reactive intermediate.
`In toluene the methyl group serves as a safe metabolic
`handle preferably attacked by the mixed function oxidases leading to benzoic acid
`as an end product. This principle is further elucidated in fig. 5.
`The objection that metabolically stable agents,
`lipophilic enough to penetrate
`the central nervous system, would not be eliminated by renal excretion can be re-
`jected for a number of reasons. Centrally active compounds excreted to a large ex-
`tent unmetabolized exist. Examples are anorectic agents, such as phentermine and
`derivatives and phenphluramine, which still have relatively short half—life times
`
`

`

`AVOIDANCE OF RISKY AROMATIC RING OXIDATION (PHENOL FORMATION) BY INTRO-
`Fig. 5.
`DUCTION OF ALTERNATIVE SAFER METABOLIC HANDLES.
`
`177
`
`
`
`The figures indicate the organic (phenolic) sulphate as a fraction of the total
`sulphate excretion in the urine (rat). High values imply ring oxidation,
`low
`values imply attack along safer metabolic pathway. The low value