PSTT Vol. 2, No.
11 November 1999
Metabolism-based drug design
and drug targeting
Laszlo Prokai and Katalin Prokai-Tatrai
Even at the early stages of drug discovery and structure-based drug de-
sign, the pharmacokinetic, pharmacodynamic and toxicological conse-
quences of drug metabolism cannot be ignored. Drug metabolism is also
of interest to medicinal chemists in the design of drugs with controlled,
predictable deactivation after achieving the therapeutic objective in
prodrug design and in chemicalenzymatic drug targeting. In this re-
view, the authors provide an overview of concepts that can be utilized
from drug discovery to pharmaceutical development to overcome prob-
lems associated with drug metabolism, or that may be used to take ad-
vantage of designed-in metabolic activation to achieve drug targeting.
Drug metabolism has several pharmaco-
Laszlo Prokai
dynamic, pharmacokinetic and toxicological con-
and Katalin Prokai-Tatrai
Centre for Drug Discovery sequences that are not judicious to ignore, even at
University of Florida the early stages of drug discovery and drug de-
J. Hillis Miller Health Center sign. Data accumulated on the metabolic conver-
Gainesville sion (toxication, activation and deactivation) of
FL 32610-0497
drugs intelligibly point to the necessity of includ-
USA
tel: 11 352 392 3421 ing considerations on metabolism in the general
fax: 11 352 392 3421 approach. Instead of concentrating on unfolding
e-mail: lprokai@grove.ufl.edu and utilizing only structureactivity relationship
(SAR) information in the process to find the lig-
and with the highest affinity to the target recep-
tor, metabolic properties of new drug candidates
as well as their pharmacodynamic, pharmacoki-
netic and toxicological consequences must also
be considered in order to maximize the thera-
peutic index (TI; the ratio between the dose that
elicits toxic side effects and the effective thera-
peutic dose) for the given drug application.
Efforts to optimize the pharmacokinetics (PK),
pharmacodynamics (PD) and/or to reduce the
toxic effects while retaining affinity to the cog-
nate receptor generally convey an increase in the
TI of drugs. In addition, a highly desired goal of
drug therapy is to concentrate the effects of the
1461-5347/99/$ see front matter 1999 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(99)00208-4
research focus reviews
therapeutic agent to the intended site of action
(organ, organelle and tissue).This overview high-
lights strategies that may be used to achieve these
important goals by involving rational, metab-
olism-based drug design.
Controlling PK/PD and toxicity
via drug metabolism
Various therapeutic objectives can only be
achieved by controlling the PK/PD of the drug.
One of the best examples involves analgesia.
Potent analgesics are used clinically during surgi-
cal procedures as adjuncts to gaseous and in-
jectable anesthetics. 4-Anilidopiperidines (fen-
tanyl and its congeners, Fig. 1), which are potent
m-opioid agonists, have been used as anesthesia
adjuncts. Alfentanil has been used as a short-act-
ing agent whose half-life in humans is 7090
min (Ref. 1), but the need for an ultra-short act-
ing opioid arose with the emphasis in surgical
and anesthetic practice focusing on shorter and
outpatient procedures. However, receptor- and
SAR-based approaches to find suitable 4-anili-
dopiperidine congeners2 were unable to identify
drug candidates that would meet the criteria for
an ultra-short acting agent.
To discover an ultra-short acting 4-anilido-
piperidine-type analgesic agent, structural modifi-
cation was involved that allowed for a rapid, sin-
gle-step metabolism in the blood to generate an
inactive compound3. Carfentanil analogues in
which the N-substituent of the piperidine nucleus
was replaced with a hydrolytically labile phenyl
bioisostere yielded potent analgesics with an ultra-
short duration of action. Based on a mathematical
model developed to explain the quantitative struc-
tureactivity profile of this series of 4-anilido-
piperidine opioids, a significant correlation existed
between the duration of pharmacological effect in
vivo and the rate constant for hydrolysis in human
blood4. Remifentanil (3-{4-methoxycarbonyl-4-
457
reviews research focus
R R'
Fentanyl H 4.6
Alfentanil CH2OCH3
N R' S
O and in vivo duration were
N measured by the tail
Carfentanil CO2CH3
R
Remifentanil CO2CH3 CO2CH3
O O
N CH3 Plasma N CH3
O esterases
O O
N O N O
O
CH3
Remifentanil
[(1-oxopropyl)phenylamino]1 piperidine}propanoic acid methyl
ester), the compound selected for pharmaceutical development, is
approximately eight times more potent than alfentanil in dogs,
and rapidly converted in one step by esterase to a metabolite
whose potency is approximately 4500-times less than that of
remifentanil5. One advantage that remifentanil has over other opi-
oid agonists, in addition to its rapid onset and peak effect
(approximately one minute) and short half-life (1020 min), is
that effects are noncumulative and recovery is rapid when admin-
istration is discontinued, regardless of the length of infusion.
Therefore, adverse effects (respiratory depression, bradycardia,
hypotension and skeletal muscle rigidity) resolve rapidly, but so
does the analgesia. Remifentanil (Ultiva, Boehringer Ingelheim,
Ingelheim, Germany and Ridgefield, CT, USA) recently received
FDA approval for intravenous indications (analgesia during induc-
tion and maintenance of general anesthesia for inpatient and out-
patient procedures; continuation analgesia into the immediate
post-operative period under the direct supervision of an anesthe-
sia practitioner in a post-operative anesthesia care unit or intensive
care setting; and analgesia during monitored anesthesia care)6.
Additional examples to involving structuremetabolism relation-
ships into the design of short-acting agents include, among oth-
ers, b-blockers7,8 and anticholinergics9,10.
Another aspect of designing drugs that are metabolized in a
controllable, one-step process to an inactive metabolite is the ap-
parent improvement of the TI, especially when topical drug ap-
plication is considered. A good example is loteprednol etabon-
458
PSTT Vol. 2, No. 11 November 1999
ED50 g/kg Duration in vivo Figure 1. 4-Anilidopiperidine
analgesic agents, including
remifentanil designed as an
60 ultra-short acting opioid due
to facile, one-step
deactivation in vivo by
4.5 55 plasma esterases. The 50%
effective dose (ED50) values
withdrawal assay in rats3.
0.5 45
4.4 15
O
O
CH3 (ED50 = 1.6 mg/kg)
ate (Lotemax and Alrex, Bausch & Lomb Pharmaceuticals,
Rochester, NY, USA), an anti-inflammatory and anti-allergic
compound derived from prednisolone (Fig. 2)11. In ophthalmic
applications for the treatment of ocular inflammation, the drug
is topically effective, but undergoes rapid conversion to inactive
metabolites by ubiquitous esterases after its therapeutic effects
have been expressed at or near the site of application12.
General approaches to the design of drug candidates that
show favourable PK/PD and toxicity profiles according to the
principles outlined above may involve various additional meth-
ods13. Close structural analogues of an active therapeutic agent
that have a specific metabolically sensitive site built into their
structure can provide one-step detoxification. Inactive metab-
olites of a lead compound may be chemically modified to build
isosteric or isoelectronic analogues amenable to facile enzymatic
conversion back to the inactive metabolite. Appropriate intro-
duction (via enzymatically labile chemical bonds) of specific
pharmacophore(s) that are responsible for eliciting the desired
biological activity into nontoxic chemical compounds may also
be used. Active drug metabolites that are already at their highest
oxidation states are usually transformed to an inactive, nontoxic
metabolite in a single step. In general, involvement of oxidative
conversion (by cytochrome P-450 isoenzymes) in drug metab-
olism should be avoided when designing new, safe therapeutic
agents. A single-step detoxification of a drug that avoids oxi-
dation reduces the toxic effect to the drugs intrinsic toxicity,
while cumulative toxic effects caused by active metabolites and
PSTT Vol. 2, No. 11 November 1999
O OCH2Cl O OH
OH OCO2C2H5 OH OCO2C2H5
Esterase
O vation of the compound. Multiple conversions may not only lead
O
Loteprednol etabonate
Relative binding affinity = 490
(Dexamethasone = 100)
Rapid deactivation by plasma
esterases leads to localized effect
High therapeutic index (~24)
Figure 2. Loteprednol etabonate, an anti-inflammatory and antiallergic
compound derived from prednisolone, and its in vivo biotransformation
designed to produce an inactive, nontoxic primary metabolite8,9.
reactive intermediates, such as radicals and epoxides obtained
during oxidative metabolism, are eliminated13. Agents subject to
facile, one-step deactivation in vivo are sometimes referred to as
soft drugs13, although this term has also been applied in an
entirely different context referring to drug abuse14.
The gradual accumulation of data from drug metabolism stud-
ies has contributed to the development of methods that attempt
to predict metabolic outcomes for new structures15, which may
be used in metabolism-based drug design considering the meth-
ods outlined above. Libraries of compounds (from corporate col-
lections, or prepared using the techniques of combinatorial
chemistry) can be filtered by using these principles for admissi-
bility before testing or may even be designed to avoid the selec-
tion of junk leads.Alternatively, metabolism-based design can be
employed during lead optimization or, perhaps, as a lead rescue.
Drug targeting by metabolism-based design
Organ- and site-targeted delivery of therapeutic agents has
been another important means to achieve an improvement in
the TI of drugs; if a systemically or orally administered drug
could be targeted only to the pathophysiologically relevant site,
not only would the efficacy be enhanced but also the toxicity
may well be controlled or greatly reduced as a result of a de-
crease in the required drug dose. However, many drugs and
drug candidates encounter biological membranes as barriers
to their targeted delivery.
Prodrug approaches that provide potential for improving drug
delivery into the target site usually utilize drug metabolism. Pro-
drugs are pharmacologically inactive compounds that usually in-
volve a single, transient chemical modification of the pharmaco-
logically active species to improve the deficient physicochemical
properties of a given drug.This method has recently been exten-
research focus reviews
sively reviewed16,17. Some of the weaknesses of prodrugs, as an
ad hoc approach to complement ligand design and discovery,
originate in the single chemical conversion occurring in the acti-
to selectivity in delivery under certain conditions, but also de-
crease the toxicity of a drug and sustain its action. The recogni-
tion of this important aspect led to the development of a chemi-
cal delivery system (CDS) concept1820. CDSs (Ref. 21), similar to
prodrugs, are also inactive compounds and are activated by sev-
eral enzymatic and/or chemical transformations to liberate the
target drugs preferentially at the site of action. In an ideal case,
the target drug is released from its CDS only in the intended
organ or tissue, but it is present in an inactive form elsewhere in
the body and is amenable to rapid elimination.
Ocular- and stereospecific drug delivery
As a result of an uneven expression of different enzymes in the or-
gans, certain enzymatic reactions can occur predominantly (or ex-
clusively) at a specific site within the body. Drug targeting that uti-
lizes ocular bioactivation may apply structural modifications to the
lead compound, which yields CDSs whose conversion to the tar-
get drug occurs only in the eye in the iris ciliary, which is partic-
ularly rich in highly active enzymes22. One of the successful ex-
amples of this approach involves b-adrenergic antagonists for the
potentially safe treatment of glaucoma.The action of b-adrenergic
antagonists is based on the reduction of the intraocular pressure
(IOP). However, these drugs were developed for their systemic
beta-blocking activity, and therefore ophthalmic application often
results in serious primary systemic side effects.
Although the eye itself is easily accessible for topical treatment,
approximately only 2% of the introduced medication will eventu-
ally be absorbed within the eye, and the rest will pass through the
nasal-lacrimal canal and then into the nasal and gastric mucosa.
This low ocular delivery and significant systemic availability may
be the reason for the systemic side effects. For example,Timolol,
the first and most widely used anti-glaucoma drug, can cause
heart rate reduction even in normal subjects after the ocular ad-
ministration of its 0.5% ophthalmic solution. In addition, several
respiratory events have been reported in connection with the ap-
plication of b-blockers. A CDS approach considered chemical
modifications of the b-adrenergic antagonists, where an oxidized
(ketone) form of the drug is derivatized to an oxime or alkoxime.
The CDS is first hydrolysed back to the ketone by an oxime hy-
drolase, followed by the reduction of the ketone to the amino al-
cohol, which represents the pharmacologically active b-blocker,
by a ketone reductase (Fig. 3). In the meantime, the inactive CDS
is not converted to the target drug in any other body compart-
ment and, thus, the peripheral side effects can be drastically re-
duced. At the same time, the intact CDS is easily eliminated from
the body.
459
reviews research focus
While the oxime hydrolysis to the original ketone is a
straightforward chemical reaction, it had been previously un-
known that this hydrolysis reaction could, indeed, occur in the
eye. Fortunately, the subsequent enzymatic reduction of the
ketone to the b-adrenergic antagonist was not only facile, but
also stereospecific, producing the active S-(-isomer)23. Highest
concentrations of the active drug were observed, as expected, in
the irisciliary body. Alternatively, intravenous administration of
several ketoxime-type CDSs of b-adrenergic antagonists did not
yield the corresponding amino alcohols and, thus, did not pro-
duce any systemic (cardiovascular) activity2426. Alprenoxime, a
ketone analogue of the drug alprenolol, emerged as a potential
drug candidate from these promising preclinical investigations.
However, the oximes were not sufficiently chemically stable in
an aqueous vehicle to provide an acceptable shelf life, therefore
necessitating formulation and storage in a lyophilized form re-
quiring reconstitution prior to use (this problem caused Phase I
clinical studies into alprenoxime to be abandoned).Thus, further
chemical modification was necessary; this time the oxime group
itself was modified. It was hypothesized that masking of the hy-
droxyl group would enhance stability by hindering the possibility
of intramolecular hydrogen bonding between the oxime and ter-
tiary amine groups, which was believed to be the main cause of
chemical instability. Obviously, it was anticipated that enhanced
chemical stability would not result in enhanced enzymatic stabil-
ity. Several methoximes were prepared in a synthetic procedure
similar to that of the corresponding oximes27. The stability of
metoxime analogues was, indeed, significantly improved (the
shelf life t90, which is the time within which only 10% of drug is
decomposed, exceeded one year at pH 7) compared with that of
corresponding oximes (at the same time, in vivo ocular hydrolysis
followed by reduction also took place)27.When the IOP-reducing
potency of methoximes was studied in normotensive rabbits, al-
prenolone methoxime resulted in a 23% decrease in one hour,
compared with a 34% drop produced by bilaterial topical admin-
istration of alprenoxime in an equal dose. Although the duration
of action for the methoxime is somewhat shorter than that of
oxime, the ocular response of the latter took three hours to fully
Ar Ar
O NHR' O NHR'
Hydrolase
NOR O charged trigonellyl moiety upon enzymatic oxidation similar to
Ketone reductase
R = H, CH3
R' = alkyl S-(-)
Ar *
O NHR'
OH
Figure 3. Stereospecific ocular targeting of b-adrenergic antagonists
by site-specific enzymatic bioactivation2327.
460
PSTT Vol. 2, No. 11 November 1999
develop and reach the maximum IOP reduction observed for al-
prenolol or its methoxime CDS.The methoxime had a prolonged
ocular hypotensive activity (four to five hours), whereas al-
prenolol only produced statistically significant IOP reduction for
two to three hours. It is also worth noting that topical adminis-
tration of the methoxime CDS (as an oxalate salt in a 60 mM iso-
tonic phosphate vehicle) did not cause the irritation observed for
alprenolol, the corresponding lead b-adrenergic antagonist.
Brain-specific drug targeting
The bloodbrain barrier (BBB) is a great impediment for drug
delivery to the brain as this lipoidal bilayer prevents the passage
of lipid-insoluble pharmaceutical agents to the central nervous
system (CNS). While drug uptake into the CNS may be facili-
tated by increasing the lipophilicity of the drug by attaching a
suitable pro-moiety and forming a prodrug, the efflux of a
lipophilic prodrug is also enhanced, which results in poor tis-
sue retention. This nonselective delivery is especially damaging
when potent drugs are considered. The combined effects of
poor selectivity, poor retention and the possibility of reactive
catabolism often results in a decrease, rather than an increase, in
the TI of the drugs when they are turned into prodrugs. Some
of the weaknesses of the prodrug approach originate, again, in
the single chemical conversion occurring in the activation of
the compound. Recognition of the importance of multiple, se-
quential metabolic steps in brain targeting of drugs by chemi-
calenzymatic methods has again led to the development of
brain-specific chemical delivery systems (CDSs) (Ref. 20).
In designing a CDS for the CNS, the unique structure of the
BBB can actually be turned to an advantage, as shown in Fig. 4.
The influx of a sufficiently lipid-soluble CDS is caused by pas-
sive transport. The CDS, which contains functional unit(s) co-
valently attached to the target drug, is then subjected to a piv-
otal enzymatic reaction in the CNS that turns off its lipophilic
character through conversion from a neutral- to an ionic-func-
tional group. As a result, the efflux of this intermediate from
the CNS is greatly hindered or, ideally, prevented. Meanwhile,
peripheral elimination of the entity is accelerated because of
this conversion of the CDS in the body. This very frequently
cited lock-in mechanism produces the CNS-selectivity.
The 1,4-dihydrotrigonellyl group, which is converted to the
that of NADH NAD, has been the most widely used moiety
for brain-targeting. After the enzymatic oxidation, additional
enzymatic and/or chemical conversion is responsible for the
release of the therapeutic agent in the CNS. CDSs that possess
these attributes have been developed in which a hydroxy,
amino or carboxylic acid-containing drug is covalently linked
to a functional group containing a 1,4-dihydropyridine unit.This
approach has been extensively applied to the enhanced delivery
PSTT Vol. 2, No. 11 November 1999
Drug Drug
(Oxidation)
Drug (+)
(Oxidation)
Drug
Drug (+)
release
Elimination Drug
Blood Brain
Bloodbrain barrier (BBB)
Pharmaceutical Science & Technology Today
Figure 4. Brain-targeting of drugs by chemical delivery systems. The
green square indicates a lipophilic functional group covalently attached
to the drug, which facilitates the entry of the conjugated drug into the
brain across the lipoidal bloodbrain barrier (BBB). Metabolism of this
targeting moiety to a hydrophilic, commonly positively charged moiety
(red square) renders the molecule lipid-insoluble, provides retention in
the brain and, simultaneously, accelerates elimination from the systemic
circulation. Drug release from the conjugate trapped behind the BBB
occurs by a subsequent metabolic step (hydrolysis)28.
to the brain of a great variety of pharmaceuticals (steroid hor-
mones, neurotransmitters, anticonvulsants, antibiotics, anti-
viral, anticancer and antidementia agents and, more recently,
neuropeptides)28. For example, the CDS approach has been
considered by numerous researchers to improve the TI of azi-
dothymidine (AZT and zidovudine) for encephalopathy associ-
ated with acquired immune deficiency syndrome (AIDS).
AIDS encephalopathy is a condition resulting from the direct
infection of the brain by the human immunodeficiency virus
(HIV). The condition affects 40% of AIDS patients29, and
8095% of autopsies reported on AIDS fatalities find that
neuropathological AIDS is also associated with several oppor-
tunistic infections that target the CNS (Refs 30,31). Neuro-AIDS
has been very difficult to treat, and this is largely because of the
inability of many potentially useful antiviral agents to reach
therapeutically significant brain concentrations upon systemic
administration. AZT, the first drug approved for the treatment of
AIDS, has been useful in improving the neuropsychiatric symp-
toms associated with AIDS encephalopathy. However, the doses
required to elicit this improvement cause severe anemia that
usually leads to the cessation of AZT-therapy32. Although AZT en-
ters the cerebrospinal fluid (CSF) and achieves significant
concentrations after oral or intravenous administration33,34, the
CSF levels may exceed brain tissue levels because the agent is ca-
pable of only poor penetration of the BBB35.
research focus reviews
AZT has a single primary alcohol function in the 59-position
that is available for the attachment of the redox targetor (Fig. 5).
The mechanism for targeting of the brain by CDSs essentially re-
lies on changes in lipophilicity caused by metabolism; there-
fore lipophilicity is an important factor that determines the ef-
ficacy of a CDS (Refs 3638). Based on the log P (the logarithm
of n-octanol/water partition coefficient, which is commonly
used to characterize lipophilicity) values, the brain-uptake of
the lipophilic CDS (log P 5 1.5) is expected to be higher than
that of AZT (log P 5 0.06), while the efflux of its metabolite,
AZTQ1 (log P 5 22.0), should be prevented from entering
the CNS; the log P values indicate that AZTCDS is 34-times
more lipophilic, and the oxidized AZTQ1 is 115-times less
lipophilic than the parent antiretroviral drug.
Evaluation of AZTCDS has been performed in animal mod-
els. The concentration of the parent drug and the CDS were
compared after intravenous administration of 0.136 mmol kg21
of AZT dose in blood and brain. Half-life in blood was approxi-
mately 20 min, and no AZT was detected after two hours. The
AZT distribution profile in the two tissues studied were also
significantly different. In the blood, the initial high level of CDS
rapidly disappeared, while no CDS was detected in the brain,
which is in agreement with its in vitro instability. The AZTQ1
concentration in the brain, however, had a sustained level,
reaching the maximum value after 15 min of administration
and then slowly declining, which is associated with AZT release
in the CNS reaching peak levels at 30 min post-drug introduc-
tion and detectable up to 120 min. The 15 min plateau is typi-
cal for dihydropyridine-type CDSs and is a result of the in vivo
conversion of the CDS to its corresponding pyridinium salt.
Following studies performed on rats, AZTCDS was also
evaluated in mongrel dogs at 11 mmol kg21 AZT, followed by a
dose of 11 mmol kg21 of the dihydropyridine-type CDS one
week later.The experimental data revealed that initial blood levels
of AZT after AZTCDS were much lower than the dose obtained
from AZT alone. By 100 min, the curves were superimposable. In
the CSF,AZTCDS produced a significant level of AZT, but reached
the above virustatic level after only 5 min (1.0 mmol l21 thera-
peutic threshold for virustatic activity) for up to three hours post-
dosing. Other studies39,40 revealed that the CDS resulted in rapid
tissue uptake, and the conversion to AZTQ1 eventually produced
AZT levels in the brain that were 1.753.3-fold higher and pro-
vided 46% lower AZT levels in blood than those associated with
conventional AZT administration. Dose-dependent brain-targeting
by AZTCDS (Refs 41,42) has also been observed. The AZT
concentration was always higher in the blood during the time pe-
riod studied than in the brain after administration of the parent
drug to New Zealand albino rabbits, but the ratio was approxi-
mately three at 60 min post-dose of the AZTCDS (Refs 43,44).
The CDS was also found to exert anti-HIV activity in vitro and to
461
reviews research focus PSTT Vol. 2, No. 11 November 1999

AZT-CDS (log P = 1.57) AZT-Q+ (log P = 2.0) 6 Med Sci Bull. (1996) 19, 1

O O
7 Erhardt, P.W. et al. (1982) J. Med. Chem. 25, 14081412
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CH3 CH3 8 Bodor, N. et al. (1988) J. Med. Chem. 31, 16511656
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The specific examples discussed in this review have highlighted 27 Prokai, L. et al. (1995) J. Med. Chem. 38, 20182020
the methods and value of metabolism-based approaches that 28 Prokai, L., Prokai-Tatrai, K. and Bodor, N. Med. Res. Rev. (in press)
may be employed to address PK/PD and toxicological outcomes 29 Navia, B., Jordan, B. and Price, R. (1986) Ann. Neurol. 19, 525535
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