0031-699779714904-0403$03.00.'0
`PHARMACOLOGICAL REVIEWS
`Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
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`Vol. 49, No. 4
`Printed in U.S.A.
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`Role of Pharmacokinetics and Metabolism in Drug
`Discovery and Development
`JIUNN H. LIN“ AND ANTHONY Y. H. LU
`
`Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania
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`I. Introduction .
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`II. Role of pharmacokinetics and metabolism in drug design .
`A. Metabolism and drug design .
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`1. Hard drugs .
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`2. Soft drugs .
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`3. Active metabolites .
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`B. Pharmacokinetics and drug design .
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`2. Prodrugs.
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`1. Absorption .
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`B. Species- and tissue—specific toxicity .
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`$-
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`3. Distribution .
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`4. Plasma half~life .
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`5. Stereoselectivity .
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`III. Role of metabolism in drug toxicity .
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`A. Species differences in metabolism .
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`1. Oxidation and conjugation .
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`2. Induction .
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`3. Inhibition .
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`4. Sexual dimorphism .
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`1. Species-specific toxicity.
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`2. Site-specific toxicity .
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`C. Stereoselectivity and toxicity .
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`1. Stereoselective metabolism .
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`2. Stereoselective toxicity .
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`IV. Role of pharmacokinetics and metabolism in drug development .
`A. In vitro studies of drug metabolism .
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`1. Determination of metabolic pathways .
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`2. Identification of drug-metabolizing enzymes .
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`3. Drug-drug interactions .
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`4. Prediction of in vivo metabolic clearance .
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`B. In vitro studies of drug absorption .
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`l. Extrapolation of in vitro absorption data .
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`2. Extrapolation of animal absorption data .
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`C. In vitro studies of protein binding .
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`1. In vitro/in vivo protein binding .
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`2. Plasma and tissue protein binding .
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`3. Protein binding displacement interactions.
`V. Interindividual variability: a critical issue in drug development .
`A. Pharmacokinetic variability .
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`1. Variability in absorption .
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`2. Variability in binding .
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`3. Variability in excretion .
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`B. Pharmacogenetics of drug‘ metabolism .
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`1. Polymorphism in drug oxidation .
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`
`M
`
`L‘
`
`“ Address for correspondence: Jiunn H. Lin, WP26A-2044, Department of Drug Metabolism, Merck Research Laboratories, West Point, PA
`19486.
`403
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2028 - 0001
`
`

`
`404
`
`LIN AND LU
`
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`2. N-acetylation polymorphism .
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`3. S—methylation polymorphism .
`4. Atypical butyrylcholinesterase .
`VI. Conclusions .
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`VII. References .
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`. .. 440
`
`I. Introduction
`
`Drug research encompasses several diverse disci-
`plines united by a common goal, namely the develop-
`ment of novel therapeutic agents. The search for new
`drugs can be divided functionally into two stages: dis-
`covery and development. The former consists of setting
`up a working hypothesis of the target enzyme or recep-
`tor for a particular disease, establishing suitable models
`(or surrogate markers) to test biological activities, and
`screening the new drug molecules for in vitro and/or in
`vivo biological activities. In the development stage, ef-
`forts are focused on evaluation of the toxicity and effi-
`cacy of new drug candidates. Recent surveys indicate
`that the average new chemical entity taken to market in
`the United States requires 10 to 15 years of research and
`costs more than $300 million.
`Once the target enzyme or receptor is identified, me-
`dicinal chemists use a variety of empirical and seIniem—
`pirical structure-activity relationships to modify the
`chemical structure of a compound to maximize its in
`vitro activity. However, good in vitro activity cannot be
`extrapolated to good in vivo activity unless a drug has
`good bioavailability and a desirable duration of action. A
`growing awareness of the key roles that pharmacokinet-
`ics and drug metabolism play as determinants of in vivo
`drug action has led many drug companies to include
`examination of pharmacokinetics and drug metabolism
`properties as part of their screening processes in the
`selection of drug candidates. Consequently, industrial
`drug metabolism scientists have emerged from their
`traditional supportive role in drug development to pro-
`vide valuable support in the drug discovery efforts.
`To aid in a discovery program, accurate pharmacoki-
`netic and metabolic data must be available almost as
`
`early as the results of the in vitro biological screening.
`Early pharmacokinetic and metabolic evaluation with
`rapid information feedback is crucial to obtain optimal
`pharmacokinetic and pharmacological properties. To be
`effective, the turnover rate needs to be at least three to
`five compounds per week for the support of each pro-
`gram. Due to time constraints and the availability of
`only small quantities of each compound in the discovery
`stage, studies are often limited to one or two animal
`species. Therefore, the selection of animal species and
`the experimental design of studies are important in pro-
`viding a reliable prediction of drug absorption and elim-
`ination in humans. A good compound could be excluded
`on the basis of results from an inappropriate animal
`species or poor experimental design.
`
`After a drug candidate is selected for further develop-
`ment, detailed information on the metabolic processes
`and pharmacokinetics of the new drug is required by
`regulatory agencies. The rationale for the regulatory
`requirement is best illustrated by the case of active
`metabolite formation. Many of the currently available
`psychotropic drugs form one or more metabolites that
`have their own biological activity (Baldessarini, 1990).
`Pharmacokinetically, the active metabolites may differ
`in distribution and clearance from that of the parent
`drug. Pharmacologically, the parent drug and its metab-
`olites may act by similar mechanisms, different mecha-
`nisms, or even by antagonism. An understanding of the
`kinetics of active metabolite formation is important not
`only for predicting therapeutic outcome, but also for
`explaining the toxicity of specific drugs.
`Conventionally, the metabolism of new drugs in hu-
`mans is studied in vivo using radiotracer techniques as
`part of clinical absorption and disposition studies. How-
`ever, this approach often occurs relatively late in the
`development stage. Ideally, the metabolism of new drugs
`should be studied in vitro before the initiation of clinical
`
`studies. Early information on in vitro metabolic pro-
`cesses in humans, such as the identification of the en-
`zymes responsible for drug metabolism and sources of
`potential enzyme polymorphism, can be useful in the
`design of clinical studies, particularly those that exam-
`ine drug-drug interactions. It is also desirable that the
`comparison of metabolism between animals and humans
`be performed in the early stage of the drug development
`process to provide information for the appropriate selec-
`tion of animal species for toxicity studies before these
`toxicity studies begin.
`The advance of in vitro enzyme systems used for drug
`metabolism studies (Wrighton and Stevens, 1992; Guil-
`louzo et al., 1993; Berry et al_, 1992; Remmel and Burch-
`ell, 1993; Brendel et al., 1990; Chapman et al., 1993),
`together with the explosion of our knowledge of various
`drug-metabolizing enzymes including uridine-diphos-
`phate-glucuronosyl-transferases (Cougletrie, 1992), cy-
`tochrome P-450s (Henderson and Wolf, 1992; Gonzalez
`and Nebert, 1990) and carboxylesterases (Wang, 1994;
`Hosokawa, 1990), allows us to obtain early information
`on the metabolic processes of new drug candidates well
`before the initial clinical studies. In addition, the advent
`of commercial liquid chromatography—mass spectrome-
`try instrumentation and the development of high-field
`nuclear magnetic resonance as well as liquid chromatog-
`raphy-nuclear magnetic resonance techniques have fur-
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2028 - 0002
`
`

`
`ROLE OF PHARMACOKINETICS AND METABOLISM IN DRUG RESEARCH
`
`405
`
`ther strengthened our capability to study the metabo-
`lism of new drugs in the early drug discovery stage
`(Fenselau, 1992; Baillie and Davis, 1993). However, the
`role of drug metabolism scientists in drug discovery is
`more than just screening compounds in vitro and in vivo.
`It really entails a good understanding of the basic mech-
`anisms of the events involved in absorption, distribu-
`tion, metabolism and excretion; the interaction of chem-
`icals with the drug-metabolizing enzymes, particularly
`cytochrome P-450; sources of pharmacokinetic and phar-
`macodynamic interindividual variability; and the conse-
`quences of metabolism on potential drug toxicities.
`The purpose of this paper is to review the role of
`pharmacokinetics and drug metabolism in drug discov-
`ery and development from an industrial perspective.
`The intent is to provide a comprehensive, rather than
`exhaustive, overview of the pertinent literature in the
`field. Several excellent review articles on individual top-
`ics are available and the reader is referred to the most
`
`recent articles in the text. It is hoped that with a better
`understanding of the fate of the drugs, a balanced in
`vitro/in vivo approach and an intelligent application of
`sound principles in pharmacokinetics and enzymology,
`drug metabolism scientists can contribute significantly
`to the development of safe and more efiicacious drugs.
`
`II. Role of Pharmacokinetics and Metabolism in
`
`Drug Design
`
`The history of the pharmaceutical industry shows that
`many important drugs have been discovered by a com-
`bination of fortuity and luck. This serendipity is best
`exemplified by the discovery of isoniazid. Isoniazid was
`first synthesized by Meyer and Mally (1912). Its antitu-
`berculosis properties were not found until 40 years later,
`when Robitzek et al.
`(1952) gave isoniazid to 92
`“hopeless” patients with progressive caseous—pneumonic
`pulmonary tuberculosis that had failed to show im-
`provement after any therapy. Furthermore, both indo-
`methacin and ibuprofen compounds were developed as
`antirheumatic agents even without any knowledge of
`their mode of action (Shen, 1972; Adams et al., 1969,
`1970). The mode of action was established several years
`after the drugs were on the market when Vane (1971)
`showed that these nonsteroidal anti-inflammatory
`drugs acted by inhibiting the synthesis of prostag1an—
`dins.
`
`Another example of serendipity is the discovery of
`anxiolytics. Diazepam and chlordiazepoxide, the most
`widely used henzodiazepines, were found to have anxio-
`lytic activity in 1958 and were marketed in 1960. Efforts
`to determine the mechanism of benzodiazepine action
`were initiated only after their introduction into the
`clinic. It was not until 1974 that convincing evidence
`from behavioral, electrophysiological, and biochemical
`experiments was accumulated to demonstrate that ben-
`zodiazepines act specifically at synapses in which y-ami-
`
`nobutyric acid (GABA)h functions as a neurotransmitter
`(Baldessarini, 1990; Haefely et al., 1985; Williams and
`Olsen, 1989).
`Over the past decades, through a better understand-
`ing of disease processes, mechanism-based drug design
`has evolved and produced drugs that interrupt specific
`biochemical pathways by targeting certain enzymes or
`receptors. This approach does not require a knowledge of
`the three-dimensional environment in which drugs act.
`Recent advances in molecular biology and protein chem-
`istry have provided pure protein in sufficient quantities
`to allow structural studies to be carried out. Visualiza-
`
`tion of these structures by sophisticated computer
`graphics has made structure-based drug design feasible.
`These rational approaches of drug design have been
`successful historically in the fields of HIV protease in-
`hibitors (Vacca et al., 1994), hepatic hydroxymethylglu-
`taryl coenzyme A reductase inhibitors (Alberts et al.,
`1980) and angiotensin—converting enzyme (ACE) inhibi-
`tors (Patchett et al., 1980).
`Today, the design of new drugs is still received by
`many medicinal chemists to mean maximization of the
`desired drug activity within certain structural limits.
`Sometimes, however, compounds that show very high
`activity in vitro may prove later to have no in vivo
`activity, or to be highly toxic in in vivo models. Lack of in
`vivo activity may be attributed to undesirable pharma-
`cokinetic properties, and the toxicity may result from
`the formation of reactive metabolites. Therefore, ratio-
`nal drug design should also take both pharmacokinetic
`and metabolic information into consideration, and the
`information should be incorporated with molecular bio-
`chemical and pharmacological data to provide well-
`rounded drug design.
`
`A. Metabolism and Drug Design
`
`From toxicological and pharmacological points of
`view, it is desirable to design a “safer” drug that under-
`goes predictable metabolic inactivation or even under-
`
`" Abbreviations: 3-MC, 3-methylcholanthrene; 6-TGN, 6-thiogua-
`nine nucleotide; ACE, angiotensin-converting enzyme; AFB, alfa-
`toxin B1; Ah, aromatic hydrocarbon; AUC, area under the curve;
`AZT, zidovudine; BBB, blood-brain barrier; CCKB cholecystokinin;
`cL, clearance; CL“ hepatic clearance; cL,,,,, intrinsic clearance; CNS,
`central nervous system; CSF, cerebrospinal fluid; DMBA, 7,12-di-
`methylbenzlalanthracene; DMBB, 5-(1,3-dimetliylbutyl)-5-ethyl bar-
`bituric acid; EM, extensive metabolize:-; fp, fraction of unbound drug
`in plasma; f,, free fraction in tissue; GABA, y-aminobutyric acid;
`GSH, glutathione; Ki, dissociation constant of an inhibitor; Kimcc,
`maximum inactivation rate constant; K,,,, Michaelis constant; K”,
`ratio of drug concentration in tissue to that in plasma after drug
`administration; L-dopa, levodopa; MPH, rnethylphenidate; NAT, N-
`acetyltransferase; NSAID, nonsteroidal anti-inflammatory agent;
`PEG, polyethelene glycol; PFDA, perfluorodecanoic acid; PM, poor
`metabolizers; PPAR, peroxisome proliferator-activated receptors;
`TMT, thio methyltransferase; TPMT, thiopurine methyltransferase;
`UDPGT, uridine diphosphoglucose transferase; Vd, volume of distri-
`bution; V,—, velocity of an enzyrnic reaction in the presence of of
`inhibitor extensive metabolizers; V,,,,,,,, maximum velocity; V0, veloc-
`ity of an enzymic reaction in the absence of inhibitor.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2028 - 0003
`
`

`
`406
`
`LIN AND LU
`
`goes no metabolism. Several approaches have been used
`for the design of safer drugs.
`1. Hard drugs. The concept of nonmetabolizable
`drugs, or so-called hard drugs, was proposed by Ariéns
`(1972) and Ariéns and Simonis (1982). The hard drug
`design is quite attractive. Not only does it solve the
`problem of toxicity due to reactive intermediates or ac-
`tive metabolites, but the pharmacokinetics also are sim-
`plified because the drugs are excreted primarily through
`either the bile or kidney. If a drug is excreted mainly by
`the kidney, the differences in the elimination between
`animal species and humans will be dependent primarily
`on the renal function of the corresponding species giving
`highly predictable pharmacokinetic Profiles using the
`allometric approach (Lin, 1995; Mordenti, 1985). A few
`successful examples of such hard drugs include bisphos—
`phonates and certain ACE inhibitors.
`Bisphosphonates are a unique class of drugs. As a
`class, they are characterized pharmacologically by their
`ability to inhibit bone resorption, whereas pharmacoki-
`netically, they are classified by their similarity in ab-
`sorption, distribution and elimination. In the clinic,
`these drugs are used in patients as antiosteolytic agents
`for the treatment of a broad range of bone disorders
`characterized by excessive bone resorption. These in-
`clude hypercalcemia of malignancy, metastatic bone dis-
`ease, Paget’s disease, and osteoporosis.
`The discovery of bisphosphonates was based on earlier
`studies of inorganic pyrophosphate by Fleisch and his
`coworkers (Fleisch et al., 1966, 1968, 1969; Fleisch and
`Russell, 1970). They found that pyrophosphate bound
`very strongly to calcium phosphate and inhibited not
`only the formation of calcium phosphate crystals, but
`also the crystal dissolution in vitro. However, pyrophos-
`phate exhibited no effect on bone resorption in vivo. This
`was later explained by the observation that pyrophos-
`phate is hydrolyzed before it reaches the site of bone
`resorption. These findings led to a search for analogs
`that would display the activities similar to pyrophos-
`phate, but would also resist enzymatic hydrolysis. It
`was found that the bisphosphonates, characterized by a
`P—O—P bond rather than the P—O—P bond of pyrophosphate,
`iiilfilled these criteria. As hard drugs, bisphosphonates are
`not metabolized in animals or humans, and the only route
`of elimination is renal excretion (Lin et al., 1991c; Lin,
`1996a). In general, these compounds are very safe with no
`significant systemic toxicity (Fleisch, 1993).
`Similarly, enalaprilat and lisinopril are considered
`hard drugs. These two ACE inhibitors undergo very
`limited metabolism and are exclusively excreted by the
`kidney (Ulm et al., 1982; Tocco et al., 1982; Lin et al.,
`1988). Unlike sulfhydryl-containing ACE inhibitors,
`such as captopril and its analogs, neither enalaprilat nor
`lisinopril exhibits significant side effects (Kelly and
`0’Malley, 1990). The most common side effects accom-
`panying the clinical use of captopril are rashes and taste
`dysfunction (Atkinson and Robertson, 1979; Atkinson et
`
`al., 1980). Similar side effects are observed with penicil-
`lamine, which is a sulflriydryl-containing heavy metal
`antagonist used extensively in the treatment of Wilson’s
`disease (Levine, 1975; Suda et al., 1993). It is therefore
`speculated that captopril
`interacts with endogenous
`sulfhydryl-containing proteins to form disulfides that
`may act as haptens, resulting in immunological reactiv-
`ity, which may be responsible for these side effects
`(Patchett et al., 1980). Enalaprilat and lisinopril were
`designed to avoid these undesirable side effects by re-
`moval of the sulfhydryl group (Patchett et al., 1980).
`Due to their poor lipophilicity, the bisphosphonates,
`enalaprilat and lisinopril, are not metabolized in vivo.
`Ironically, the poor lipophilicity of these compounds re-
`sults in poor oral absorption. For the bisphosphonate
`alendronate, the octanol/buffer partition coefficient is
`0.0017 (Lin, 1996a). As a result of its poor lipophilicity,
`alendronate has very poor oral bioavailability in hu-
`mans (< 1%) (Lin, 1996a). To our knowledge, bisphos—
`phonates are the only class of drugs being developed for
`oral dosage in spite of their poor bioavailability (Lin,
`1996a). This is because the systemically available
`bisphosphonates are largely taken up by the target
`(bone) tissues, where their elimination is very slow (Lin,
`1996a, 1992, 1993b). The half-life of alendronate in bone
`was estimated to be at least 10 years in humans.
`Like bisphosphonates, both enalaprilat and lisinopril
`have low lipophilicity. The octanol-to-water partition co-
`efficient is approximately 0.003 for both drugs (Ondetti,
`1988). Interestingly, enalaprilat, a diacid compound
`with a net negative charge, is poorly absorbed (<10%),
`whereas lisinopril, a zwitterionic compound, has accept-
`able oral absorption (~30%) (Ulm et al., 1982; Tocco et
`al., 1982). Consequently, enalaprilat was developed as
`its ethyl ester prodrug (enalapril) to increase its bio-
`availability, whereas the prodrug approach was not em-
`ployed for lisinopril.
`Bisphosphonates and these two carboxyalkyldipeptide
`ACE inhibitors were not intentionally designed as hard
`drugs. The “hardness” came about only as a result of
`structural improvement. It so happens that the newer
`ACE inhibitors, such as benazepril, perindopril, and
`fosinopril, undergo significant metabolism (Kelly and
`O’Ma1ley, 1990).
`Although metabolically inert compounds are highly
`desirable candidates for drug design, the versatility of
`the drug-metabolizing enzymes presents quite a chal-
`lenge to achieve this goal. For example, cytochrome
`P-450s are known to catalyze numerous oxidative reac-
`tions involving carbon, oxygen, nitrogen, and sulfur at-
`oms in thousands of substrates with diverse structures.
`
`In addition, cytochrome P-4503 are unique in that met-
`abolic switchings can occur when the primary metabolic
`site of a compound is blocked. Thus, considering the
`broad substrate specificities and the versatilities of cy-
`tochrome P-450s and other drug-metabolizing enzymes,
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2028 - 0004
`
`

`
`ROLE OF‘ PHARMACOKINETICS AND METABOLISM IN DRUG RESEARCH
`
`407
`
`designing drug candidates that are metabolically inert
`may not always be feasible.
`2. Soft drugs. In contrast to the concept of hard drugs,
`Bodor (1984, 1982) and Bodor et al. (1980) have proposed
`the approach of soft drugs. A soft drug is pharmacolog-
`ically active as such, and it undergoes a predictable and
`controllable metabolism to nontoxic and inactive metab-
`
`olites. The main concept of soft drug design is to avoid
`oxidative metabolism as much as possible and to use
`hydrolytic enzymes to achieve predictable and control-
`lable drug metabolism. Most oxidative reactions of drugs
`are mediated by hepatic cytochrome P—450 enzyme sys-
`tems that are often affected by age, sex, disease, and
`environmental factors, resulting in complex biotransfor-
`mation and pharmacokinetic variability (Hunt et al.,
`1992; Soons et al., 1992). In addition, P-450 oxidative
`reactions have the potential to form reactive intermedi-
`ates and active metabolites that can mediate toxicity
`(Guengerich and Shimada, 1993). These undesirable ef-
`fects attributed to oxidative metabolism may be circum-
`vented to some extent by incorporating metabolic struc-
`tural “softness.”
`
`Bodor and his colleagues (Bodor, 1984, 1982; Bodor et
`al., 1980) have designed soft quaternary—type drugs con-
`taining three structural components: an acidic group, an
`aldehyde, and a tertiary amine. Upon absorption, the
`soft quaternary drugs are hydrolyzed to three nontoxic
`components that are rapidly eliminated from the body.
`Atracurium, a nondepolarizing muscle relaxant, can
`be considered a soft drug. This drug contains quaternary
`N—functions and ester groups. Atracurium is metabo-
`lized in vivo by two nonoxidative processes: a nonenzy—
`matic metabolism by Hofmann-degradation to form a
`tertiary amine and an alkene, and hydrolysis of the ester
`groups by esterases (Mutschler and Derendorf, 1995;
`Hughes and Chapple, 1981).
`Remifentanil, a novel short-acting p.—opioid receptor
`agonist, may also be considered a soft drug. This drug is
`a methyl ester and is metabolized extensively by ester-
`ases to an inactive acid metabolite, GI—90291, of which
`over 90% is subsequently recovered in urine. To a much
`lesser extent, the drug also is metabolized by N-dealky-
`lation to a second metabolite, GI-94219 (Feldman et al.,
`1991; Biirkle et al., 1996; Glass, 1995). The major me-
`tabolite GI—90291 is approximately 2000- to 4000—fold
`less potent compared with remifentanil. Although both
`hard and soft drug designs are of academic interest,
`there are only a few successful examples in the drug
`market.
`
`3. Active metabolites. For many years, the process of
`biotransformation was considered synonymous with the
`inactivation of pharmacologically active compounds.
`There is increasing evidence, however, that the metab-
`olites of some drugs are pharmacologically active. Nu-
`merous examples of pharmacologically active metabo-
`lites being used as a source of new drug candidates exist
`
`because these metabolites often are subject to phase II
`reactions and have better safety profiles.
`Perhaps the best known example is acetaminophen,
`which is an O-deethylated metabolite of phenacetin.
`Acetaminophen shows superior analgesic activity when
`compared with phenacetin. The main advantage of acet-
`aminophen over phenacetin is that it does not produce
`methemoglobinemia and hemolytic anemia (Flower et
`al., 1985). Phenacetin is converted to at least 1 dozen
`metabolites by O-deethylation, N—deacetylation, and hy-
`droxylation processes. N—hydroxyphenatidine, a metab-
`olite of phenacetin, has been shown to be responsible for
`the formation of methemoglobin and hemolysis of red
`blood cells (Jensen and Jollow, 1991). Conversely, acet-
`aminophen primarily undergoes glucuronidation and
`sulfation exclusively and is quite safe clinically at the
`recommended dose. Similarly, the analgesic oxyphen-
`butazone is an active para—hydroxy metabolite of phe-
`nylbutazone. Similar to acetaminophen, this active me-
`tabolite also shows better analgesic activity than
`phenylbutazone and causes less gastric irritation (Flow-
`er et al., 1985).
`Although pharmacologically active metabolites are
`generally formed by phase I oxidative reactions, phase II
`conjugation reactions also can produce biologically ac-
`tive metabolites. Morphine 6—glucuronide is more potent
`as a pxopioid receptor agonist than morphine itself (Paul
`et al., 1989; Mulder, 1992). Recent clinical studies in
`cancer patients given morphine 6-glucuronide indicated
`that useful analgesic effects are achieved without the
`side effects of nausea and vomiting that are often asso-
`ciated with morphine (Osborne et al., 1992). These find-
`ings have led to the commercial marketing of morphine
`6—glucuronide. Sulfation also produces biologically ac-
`tive metabolites. Minoxidil, a potent vasodilator,
`is a
`good example. Studies concerning the action of minoxidil
`revealed that the therapeutic activities were mediated
`by its sulfate conjugate (Bray and Quast, 1991).
`In addition to the advantages that active metabolites
`may have in terms of efficacy with fewer unwanted side
`effects, active metabolites can also be preferred over the
`parent drugs for kinetic reasons. Many benzodiazepines
`form active metabolites with similar pharmacological
`properties. Oxazepam is the common active metabolite
`of chlordiazepoxide, halazepam, chlorazepate, and diaz-
`epam (Caccia and Garattini, 1990). Unlike other benze-
`diazepines, oxazepam undergoes only glucuronidation
`and has a shorter half-life than any of its precursors.
`This kinetic advantage has led to the marketing of ox-
`azepam as a short—acting benzodiazepine in the treat-
`ment of sleeping disorders (Baldessarini, 1990).
`
`B. Pharmacokinetics and Drug Design
`
`Many of the failures of drug candidates in develop-
`ment programs are attributed to their undesirable phar-
`macokinetic properties, such as too long or too short tn/2,
`poor absorption, and extensive first-pass metabolism. In
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2028 - 0005
`
`

`
`408
`
`LIN AND LU
`
`a survey, Prentis et al. (1988) reported that of 319 new
`drug candidates investigated in humans, 77 (40%) of the
`198 candidates were withdrawn due to serious pharma-
`cokinetic problems. This high failure rate illustrates the
`importance of pharmacokinetics in drug discovery and
`development.
`To ensure the success of a drug’s development, it is
`essential that a drug candidate has good bioavailability
`and a desirable tie. Therefore, an acc