Pharmacokinetics: Basics to Applications

354 Pages·2022·5.932 MB·English

by  Biswajit Mukherjee

Biswajit Mukherjee
Pharmacokinetics:
Basics
to Applications
Pharmacokinetics: Basics to Applications
Biswajit Mukherjee
Pharmacokinetics: Basics
to Applications
BiswajitMukherjee
DepartmentofPharmaceuticalTechnology
JadavpurUniversity
Kolkata,WestBengal,India
ISBN978-981-16-8949-9 ISBN978-981-16-8950-5 (eBook)
https://doi.org/10.1007/978-981-16-8950-5
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My beloved parents, whose love, affection,
and blessings have always taught me to
possess perseverance, dedication, devotion,
and sincerity.
Preface
Pharmacokinetics:BasicstoApplicationsisatextbook-cum-comprehensiveguide-
bookforstudentsandresearchersofversatilefieldsofpharmaceuticalandbiomedi-
cal sciences that deal with pharmacokinetics as a subject and its application in
research, industry, and clinical investigations. The book can be beneficial for
undergraduate, graduate, and postgraduate students of pharmacy, pharmaceutical
sciences, pharmaceutical technology, clinical pharmacy, pharmacy practice, medi-
cine, faculties of the fields, researchers/scientists of pharmaceutical industries, and
persons engaged in clinical investigations. I have initially introduced pharmacoki-
netics,followedbytheideaofdifferentpharmacokineticparametersandthefunda-
mental pharmacokinetic phenomena—absorption, distribution, metabolism, and
elimination (ADME), including nonlinear kinetics. The explicit knowledge of the
extent of drug absorption, bioavailability, clearance, bioequivalence, and protein
binding, pharmacokinetic drug–drug interactions are also the parts of the book
content.Ihavealsoexplainedtheapplicationofthesubjectinpreclinicalandclinical
study designing and experiments. Right from the sample collection to its analysis,
statistical data analysis guidelines, and the awareness of pharmacokinetic software
have been included in the book. Various up-to-date pharmacokinetic experiments
and the procedure of seeking clinical approval and clinical data collections have
been included to provide real-time ideas and knowledge of the subject to make
studentswellequippedtobetruepharmacokineticprofessionals.Finally,numerical
problems and questions and answers have been incorporated to assist students in
understandingandpracticingthecriticalaspectsofthechaptersforexaminations.
Myprimaryintentioninwritingthebookistopresentacomplexsubjectinone
easy way by sharing a vast more than 25 years of university-level teaching and
research experience in the field. In its originality, the book can guide its readers
through the sequential steps of learning pharmacokinetics quickly in a lucid lan-
guage.Ihavealwaysgiventhesubstantialeffortandminutecaretoavoidunneces-
sarilymakingitcomplextothereaders.Adequateandrequisiteinformationhasbeen
included in the book. All the equations are vividly described without missing or
jumpinganysteps.Itwoulddefinitelyhelpthebeginnerstothesubjecttounderstand
and learn pharmacokinetics quite easily. This book has lots of illustrations, a few
photographs,andnecessarytables thatfurtherbuildthedeepfoundationandbetter
clarification of the subject to a reader. All the figures have been self-drawn by the
author alone so that the correct intended message through the illustrations can
vii
viii Preface
nourish the inquisitive minds of the readers. A few unpublished photographs have
alsobeenincorporated.Ittooklittlemorethan8670htocompletethebook.Ityped
the entire book materials by myself to avoid mistakes or minimize the number of
mistakes significantly. The information is being shared to clarify my dedication,
devotion,andeffortsinstilledinthebooktoinculcatetheknowledgeofthesubject
with an easy presentation in pupils. I wrote the book based on the classical and
pioneeringworkandsomesignificantcurrentreportstobalanceandfinelytunethe
knowledge. Since it is a textbook, priority has been given to the established, well-
acceptedknowledge.Necessaryfundamentalmathematicsandstatisticsforeasyand
faster deduction and understanding of the equations have been incorporated in the
book.Thesinglebookwouldguidethestudentsinallnecessarylearningrelatedto
betterassimilatingthesubjectknowledgewithoutadditionalsupport.
Isincerelythankalltheresearcherswhohaveenrichedthefield,particularlythose
whosepublicationshavebeenconsideredinwritingthebook.Ofcourse,withoutthe
support of my family members, it could have been impossible for me to write this
book.Finally,Ibelievethatthisexplicitlypresentedknowledgeofpharmacokinetics
willhelpthestudentsacquirethefoundationofpharmacokineticsandthegrowthof
thesubjectknowledgeanditsapplicationsinthefield.
Kolkata,India BiswajitMukherjee
Acknowledgment
Tomybelovedwife,andlovelysonanddaughterfortheirendlesslove,support,and
encouragement,withoutwhichitwouldbehardformetocompletethebook
ix
Contents
1 FundamentalsofPharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 FundamentalsofPharmacokinetics. . . . . . . . . . . . . . . . . . . . . . 1
1.1.1 PharmacokineticParametersandBloodDrug
Profile. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.1.2 Multiple-DoseRegimen. . . . . . . . . . . . . . . . . . . . . . 7
1.1.3 ApparentVolumeofDistributionorVolumeof
Distribution(v ). . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
d
1.1.4 Steady-StatePlasmaConcentrationofDrug. . . . . . . . 12
1.1.5 DrugAccumulationFactor. . . . . . . . . . . . . . . . . . . . 15
1.1.6 Krüger-Thiemer’s“PharmacokineticFactor”. . . . . . . 17
1.1.7 Krüger-ThiemerDoseRatio. . . . . . . . . . . . . . . . . . . 17
1.1.8 ConceptofaLoadingDose. . . . . . . . . . . . . . . . . . . . 18
1.1.9 RelationshipBetweenEliminationRateConstant
(K )andSteady-StateDrugPlasmaConcentration
E
(c )fromKrüger-ThiemerDoseRatioConcept. . . . . 18
ss
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2 DrugAbsorption. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.1 DrugAbsorptionandDeterminationofDrugAbsorption
RateConstant“K ”. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
a
2.1.1 DominguezEquationandItsImportance. . . . . . . . . . 22
2.1.2 Wagner–NelsonEquationandMethod
ofDeterminationofDrugAbsorptionRate
Constant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.1.3 DeterminationofAbsorptionRateConstant
(K )fromUrinaryExcretionData. . . . . . . . . . . . . . . 25
a
2.1.4 NelsonEquation. . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.1.5 WagnerandNelsonEquation. . . . . . . . . . . . . . . . . . 27
2.1.6 Loo–RiegelmanMethodforDetermination
ofDrugAbsorptionRate(K ). . . . . . . . . . . . . . . . . . 28
a
xxii
xii Contents
2.1.7 MethodofResidualforDetermination
ofDrugAbsorptionRate. . . . . . . . . . . . . . . . . . . . . . 31
2.1.8 Flip-FlopPhenomenon. . . . . . . . . . . . . . . . . . . . . . . 32
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3 ExtentofDrugAbsorption:Bioavailability,Clearance,
Bioequivalence,andProteinBinding. . . . . . . . . . . . . . . . . . . . . . . . 37
3.1 ExtentofDrugAbsorption:Bioavailability. . . . . . . . . . . . . . . . 37
3.1.1 RenalClearance. . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.1.2 DeterminationofAbsoluteBioavailability. . . . . . . . . 39
3.1.3 DeterminationofAbsoluteBioavailability
byUrinaryExcretionData. . . . . . . . . . . . . . . . . . . . 41
3.1.4 Bioequivalence.. . . . . . . . .. . . . . . . . .. . . . . . . . .. 42
3.1.5 Drug–ProteinBinding. . . . . . . . . . . . . . . . . . . . . . . . 45
3.1.6 ReciprocalPlotorKlotzReciprocalPlot. . . . . . . . . . 46
3.1.7 ScatchardPlot. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.1.8 SandbergPlot. . .. . . . . .. . . . . . .. . . . . .. . . . . .. . 48
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4 PharmacokineticModelsandDrugDistribution. . . . . . . . . . . . . . . 51
4.1 VariousPharmacokineticModelsandDrugDistribution. . . . . . 51
4.1.1 PhysiologicalPharmacokineticModel
(FlowModel). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
4.1.2 BloodFlow–LimitedPhysiologicalPharmacokinetic
ModelorPerfusionModel. . . . . . . . . . . . . . . . . . . . 54
4.1.3 PhysiologicalPharmacokineticModelwith
Drug–ProteinBinding. . . . . . . . . . . . . . . . . . . . . . . . 58
4.1.4 Membrane-LimitedModelorDiffusion-Limited
Model. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.1.5 StatisticalMomentTheory. . . . . . . . . . . . . . . . . . . . 60
4.1.6 CompartmentModels. . . . . . . . . . . . . . . . . . . . . . . . 61
4.1.7 SomeMathematicalApproachesforEasy
ComputationofCompartmentalEquations
andTheirApplications. . . . . . . . . . . . . . . . . . . . . . . 63
4.1.8 DetailsAboutCompartmentModels. . . . . . . . . . . . . 84
4.1.9 DrugDistributionStudyThroughCompartmental
Models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5 DrugMetabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.1 DrugMetabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.1.1 HepaticDrugMetabolism. . . . . . . . . . . . . . . . . . . . . 111
5.1.2 PharmacokineticCompartmentalModels
andEquationsforAssessingHepatic“First-Pass”
EffectofaDrug. . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.1.3 HepaticFirst-PassEffectInvariablyReduces
TotalBioavailabilityofaDrugMoreWhen
AdministeredOrallythanByItsIntravenousRoute
ofAdministration. . . . . . . . . . . . . . . . . . . . . . . . . . . 115