Pharmacokinetic profiling in drug research: biological, physicochemical, and computational strategies

505 Pages·2006·24.11 MB·English

by  Bernard Testa

Pharmacokinetic Profiling
in Drug Research
Biological, Physicochemical, and
Computational Strategies
V
H A
C
Pharmacokinetic Profiling in Drug Research.
Edited by B. Testa, S. D. Krämer, H. Wunderli-Allenspach, G. Folkers
Copyright © 2006 Verlag Helvetica Chimica Acta, Postfach, CH-8042 Zürich, Switzerlaand
ISBN: 978-3-906390-35-2
Pharmacokinetic Profiling
in Drug Research
Biological, Physicochemical,
and Computational Strategies
Bernard Testa, Stefanie D. Krämer,
Heidi Wunderli-Allenspach, Gerd Folkers (Eds.)
V
H A
C
Verlag Helvetica Chimica Acta · Zürich
Prof. Bernard Testa Prof. Heidi Wunderli-Allenspach
Pharmacy Department Institute of Pharmaceutical Sciences
University Hospital Centre Dept. of Chemistry and Applied Biosciences
CHUV - BH 04 Swiss Federal Institute of Technology
46 rue du Bugnon ETH Hönggerberg, HCI H490
CH-1011 Lausanne CH-8093 Zürich
Dr. Stefanie D. Krämer Prof. Gerd Folkers
Institute of Pharmaceutical Sciences Institute of Pharmaceutical Sciences
Dept. of Chemistry and Applied Biosciences Swiss Federal Institute of Technology
Swiss Federal Institute of Technology ETH Zentrum, STW/C17
ETH Hönggerberg, HCI G490.2 Schmelzbergstr. 25
CH-8093 Zürich CH-8092 Zürich
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Preface
ThetwoSymposiaorganizedattheUniversityofLausanneinMarch
1995and2000metwithconsiderablesuccess,andthetworesultingbooks
[1][2]continuetoreceivefrequentcitation.InMarch2004, LogP2004–
The Third Lipophilicity Symposium was organized at the Swiss Federal
Institute of Technology (ETH) in Zurich as a logical sequel. Its theme
(Physicochemical and Biological Profiling in Drug Research) is of the
greatestcurrentsignificanceindrugresearch.Atotalof26invitedlectures
and94 freecommunicationswerepresented,mostofthelatterbeingalso
submitted for inclusion in the attached CD-ROM. The book with its 28
chaptersandtheCD-RomformtheProceedingsoftheSymposium.
Informatics and robotics are the workhorses of a technological revo-
lutionindrugresearch.Onthemarebasedcombinatorialchemistrywhich
yieldscompoundsbythemanythousands,andhigh-throughputbioassays
whichscreenthemforbioactivity.Theresultsareavalanchesofhitswhich
invadethedatabaseslikeswarmsoflocusts.Butfarfrombeingaplague,
theseinnumerablehitsbecomeablessingifproperlyscreenedfor(cid:1)drug-
ability(cid:2),i.e.,for(cid:1)drug-like(cid:2)propertiessuchasgoodpharmacokinetic(PK)
behavior. Pharmacokinetic profiling of bioactive compounds has thus
become a sine qua non condition for cherry-picking the most-promising
hits. Just as important, but less visible, are the structure–property and
structure–ADME relationships which emerge from PK profiling and
provideusefulfeedbackwhendesigningnewsyntheticseries.
Absorption,distribution,metabolism,andexcretion(ADME)arethe
focusofthisbook.SincethepreviousSymposiumin2000,manyadvances
have been made both in methods and concepts, and many impressive
successes have been reported. Schematically, they can be categorized as
biological, physicochemical, or computational strategies. Recently, a
synergisticuseofthesevariousstrategieshasemergedundertheincombo
roof, i.e., combined and multidisciplinarity approaches whose potential
goeswellbeyondthatoftheindividualmethodologies.
Thebookisstructuredaccordingtothesethreestrategies,themselves
framed by two introductory and two concluding chapters. In the first
introductorychapter,DavidTriggletakesabird-eyeviewofscientificand
societalissuesindrugresearch.HanvandeWaterbeemdthennarrowsthe
focusbytakingagloballookatproperty-basedleadoptimization.
PartIIisdedicatedtomajorbiologicalstrategiesinADMEprofiling.
Theroleandsignificanceofmembranesreceiveanin-depthtreatmentin
Ole G. Mouritsen(cid:2)s chapter. The state of the art in cell cultures as
absorptionmodelsisexaminednextbyArturssonandMatsson.Thetwo
VI
PREFACE
following chapters present an expert(cid:2)s view on the tools used in early
metabolicscreening(Waltherandco-workers),andontheassessmentofa
candidate(cid:2)scapacitytoinducedrug-metabolizingenzymes(Meyeretal.).
The significance of uptake and efflux transporters is gaining an ever
increasingrecognitionindrugresearchandisexpertlyreviewedhereby
Kusuhara and Sugiyama. The newly recognized role of plasma protein
bindingindrugdiscoveryisgivenconvincingtreatmentinthenextchapter
byFesseyetal.PartIIconcludeswithaninsightfultheoreticalchapteron
invivopharmacokineticprofiling.
PartIIIcoversrecentadvancesinthephysicochemicalstrategiesused
topredicttheADMEprofileofbioactivecompounds.Automatedparallel
synthesisisconsideredfirst,withamarkedemphasisondrug-likefeatures.
The connected properties of ionization and lipophilicity continue to
occupyasignificantportionofthescene,asinsightfullydiscussedbyCaron
and Ermondi. A novel HPLC technology to assess lipophilicity is
presented by Lombardo et al., while the role of lipid bilayers as perme-
ationbarriersreceivesanaptrecognitioninthenextchapter.ThePAMPA
technology has progressed markedly since the last symposium, as
explainedbyAvdeef.Interestingly,PAMPApermeationiscorrelatedwith
somelipophilicityparameters,asdemonstratedbyComerandco-workers.
Predicting the intestinal solubility of poorly soluble drugs is a challenge
facedhead-onbyDressmanandherco-workersinthenextchapter.Part
IIIthenendswithtwochapterscoveringproperties,whichuntilrecently
were in the province of late drug development and are now receiving
earlierattention,namelychemicalstability(KernsandDi)andsolid-state
properties(Giron).
Part IV is devoted to many recent advances in the computational
strategies that are having such a major impact on early predictions of
physicochemical and pharmacokinetic profiles. This part opens with an
overview by Mannhold, who offers a systematic overview of traditional
andrecentmethodstocalculatelipophilicity.Inthenextchapter,Vistoliet
al. present and illustrate a concept, whose significance in structure–
activity relationships remains to be better understood and recognized,
namely the property space of molecules. Predicting the interactions
betweenbioactivecompoundsanddrug-metabolizingenzymesisatopic
ofthehighestimportanceindrugdiscovery,andnolessthanfourchapters
are devoted to it. The computation of pharmacophores to predict
biotransformation is exemplified by Cruciani etal., and by Clement and
G(cid:1)ner.Barbosaandherco-workersshowhowenzymeinhibitioncanbe
predictedbasedonlargedatabases.Judsonthenpresentsanexpertsystem
createdanddevelopedtoofferglobalpredictionsofdrugmetabolism.A
higher order of biological complexity is covered in the chapter by Lav(cid:2)
VII
PREFACE
etal.,whodiscussphysiologicallybasedpharmacokineticmodels.Thelast
chapter in Part IV is a dense and demanding presentation of a very
powerfulin-housenetworkofexpertsystemstoprocessthefloodofdata
generatedduringbiopharmaceuticalprofiling.
Thetwoconcludingchaptersopenthereader(cid:2)shorizonbyaddressing
twoessentialissuesinPKprofiling.First,Borchardtsummarizeshisviews
on the education of, and the communication among, scientists in drug
discovery.Cautreelsetal.thenofferprovocativeideasonthepresentand
futuresignificanceofADMETprofilinginindustrialdrugresearch.
ThemissionofADMEprofilingistoincreasetheclinicalrelevanceof
drugdesign,andtoeliminateassoonaspossiblecompoundswithunfav-
orable physicochemical properties, pharmacokinetic profiles or toxicity.
Theobjectiveofthisbookistoshowhowmoderndrugresearchachieves
this mission. International authorities and practicing experts from
academiaandindustryhavebeengenerouswiththeirtimeandofferstate-
of-the-artpresentationsofconcepts,methods,andtechnologiesnowinuse
ordevelopmentindrugresearch.
Thebookwouldnotexistwereitnotforhelpgivenbythemembersof
our Scientific and Advisory Board, the technical organizers of the
Symposium, the graduate students of the Pharmacy Department at the
ETH,andvariousinstitutionsandsponsors.Editingthisvolumehasbeen
a challengeanda memorableexperience. Wehopethatourreaderswill
finditasourceofinformation,knowledge,andinspiration.
TheEditors
REFERENCES
[1] (cid:1)Lipophilicity in Drug Action and Toxicology(cid:2), Eds. V. Pliska, B. Testa, H. van de
Waterbeemd,VCHPublishers,Weinheim,1996.
[2] (cid:1)Pharmacokinetic OptimizationinDrugResearch:Biological, Physicochemical, and
ComputationalStrategies(cid:2),Eds.B.Testa,H.vandeWaterbeemd,G.Folkers,R.Guy,
VerlagHelveticaChimicaActa,Zurich,2001.
Contents
Part I. Setting the Scene
Pharmaceutical Research: For What, for Whom? 3
Science and Social Policies
David J. Triggle
Property-Based Lead Optimization 25
Han van de Waterbeemd
Part II. Biological Strategies
Membranes – From Barriers to Magic Bullets 49
Ole G. Mouritsen
Cell Culture Absorption Models – State of the Art 71
Per Artursson* and P(cid:3)r Matsson
Metabolic Studies in Drug Research and 79
Development
Benjamin Neugnot, Marie-Jeanne Bossant,
Fabrice Caradec, and Bernard Walther*
In vitro, in vivo, and in silico Approaches to Predict 93
Induction of Drug Metabolism
Urs A. Meyer*, Sharon Bl(cid:3)ttler, Carmela Gnerre,
Mikael Oscarson, Anne-Kathrin Peyer,
Franck Rencurel, Oktay Rifki, and Adrian Roth
Coordination of Uptake and Efflux Transporters in 105
Drug Disposition
Hiroyuki Kusuhara* and Yuichi Sugiyama
The Role of Plasma Protein Binding in Drug 119
Discovery
Roger E. Fessey*, Rupert P. Austin, Patrick Barton,
Andrew M. Davis, and Mark C. Wenlock
X
CONTENTS
In vivo Pharmacokinetic Profiling of Drugs 143
Heidi Wunderli-Allenspach
Part III. Physicochemical Strategies
Automated Parallel Synthesis in Support of Early 155
Drug Discovery: Balancing Accessibility of
Chemistry with the Design of Drug-Like Libraries
Carmen M. Baldino
New Insights into the Lipophilicity of Ionized 165
Species
Giulia Caron* and Giuseppe Ermondi
Physicochemical and Biological Profiling in Drug 187
Research. ElogD 20,000 Compounds Later:
7.4
Refinements, Observations, and Applications
Franco Lombardo*, Marina Y. Shalaeva,
Brian D. Bissett, and Natalya Chistokhodova
Lipid Bilayers in ADME: Permeation Barriers and 203
Distribution Compartments
Stefanie D. Kr(cid:3)mer
High-Throughput Solubility, Permeability, and the 221
MAD PAMPA Model
Alex Avdeef
Correlations between PAMPA Permeability and 243
logP
Karl Box, John Comer*, and Farah Huque
PredictingtheIntestinalSolubilityofPoorlySoluble 259
Drugs
Alexander Glomme, J. M(cid:3)rz, and
Jennifer B. Dressman*
Accelerated Stability Profiling in Drug Discovery 281
Edward H. Kerns* and Li Di
XI
CONTENTS
PhysicochemicalCharacterizationof theSolidState 307
in Drug Development
Danielle Giron
Part IV. Computational Strategies
Calculation of Lipophilicity: AClassification of 333
Methods
Raimund Mannhold
The Concept of Property Space: The Case of 353
Acetylcholine
Giulio Vistoli*, Alessandro Pedretti, Luigi Villa, and
Bernard Testa
Prediction of Site of Metabolism in Humans: Case 367
Studies of Cytochromes P450 2C9, 2D6, and 3A4
Gabriele Cruciani*, Riccardo Vianello, and
Ismael Zamora
Use of Pharmacophores in Predictive ADME 381
Omoshile O. Clement* and Osman F. G(cid:1)ner
The BioPrint(cid:3) Approach for the Evaluation of 395
ADMET Properties: Application to the Prediction
of Cytochrome P450 2D6 Inhibition
Rafael Gozalbes*, Fr(cid:2)d(cid:2)rique Barbosa*,
Nicolas Froloff*, and Dragos Horvath
Using Computer Reasoning about Qualitative and 417
Quantitative Information to Predict Metabolism
and Toxicity
Philip Judson
Physiologically Based Pharmacokinetic Models 431
Thierry Lav(cid:2)*, Hannah Jones, Nicolas Paquerau,
Patrick Poulin, Peter Theil, and Neil Parrott