Drug Targeting Organ-Specific Strategies

Contents XXIII

9.4Tumour Vasculature targeting Potentials: Extrapolation of Animal Studies

	to the Human Situation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .			250
9.5	Summary and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . .			251
References . .		. . . . .	. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	251
10	Phage Display Technology for Target Discovery in Drug Delivery Research
	Ricardo Mutuberria, Jan-Willem Arends, Arjan W. Griffioen,
	Hennie R. Hoogenboom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .			255
10.1	Introduction . .		. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	255
10.2	Phage Display Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . .			255
	10.2.1	Introduction to the Technology . . . . . . . . . . . . . . . . . . . . .		255
	10.2.2	Phage Display Libraries . . . . . . . . . . . . . . . . . . . . . . . . .		258
		10.2.2.1	Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .	258
		10.2.2.2	Peptide Display . . . . . . . . . . . . . . . . . . . . . . . . .	259
		10.2.2.3	Antibody Display . . . . . . . . . . . . . . . . . . . . . . . .	260
		10.2.2.4	Protein Scaffolds . . . . . . . . . . . . . . . . . . . . . . . .	261
		10.2.2.5 Engineering Proteins with Phage Libraries . . . . . . . . .		262
		10.2.2.6	cDNA Expression Libraries . . . . . . . . . . . . . . . . . .	262
10.3	Generation of Ligands Amenable for Targeting . . . . . . . . . . . . . . . . .			263
	10.3.1 Selection of Ligands to Defined Targets . . . . . . . . . . . . . . . . .			263
	10.3.2 Phage Display for Target Identification . . . . . . . . . . . . . . . . .			264
		10.3.2.1 In Vitro Selections on Complex Antigens . . . . . . . . . .		264
		10.3.2.2	In Vivo Selections and Selections for Functional Activity .	266
10.4	Engineering and Optimization for Targeting . . . . . . . . . . . . . . . . . . .			266
10.5	Discovery of Novel Therapeutics Using Phage Display Technology . . . . . .			268
10.6	Conclusions . .		. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	270
References . .		. . . . .	. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	270
11	Development of Proteinaceous Drug Targeting Constructs Using Chemical
	and Recombinant DNA Approaches
	Robbert J. Kok, Sigridur A. Ásgeirsdóttir, Willem R. Verweij . . . . . . . . . .			275
11.1	Introduction . .		. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	275
11.2	The Carrier . .		. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	276
	11.2.1	Albumin	. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	277
	11.2.2	Low Molecular Weight Proteins . . . . . . . . . . . . . . . . . . . . .		277
	11.2.3	Monoclonal Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . .		278
	11.2.4	Transferrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		278
11.3	The Homing Device . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .			279
	11.3.1	Carbohydrate Ligands . . . . . . . . . . . . . . . . . . . . . . . . . .		280
	11.3.2	Folate .	. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	281
	11.3.3	Peptide Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		281

XXIV	Contents
	11.3.4	Modifications of the Physicochemical Properties of the Protein . . .		282
11.4	The Active Drug		. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	283
11.5	The Linkage Between Drug and Carrier . . . . . . . . . . . . . . . . . . . . .			285
	11.5.1	Intracellular Degradation . . . . . . . . . . . . . . . . . . . . . . . . .		287
	11.5.2	Extracellular Degradation . . . . . . . . . . . . . . . . . . . . . . . .		291
11.6	Recombinant DNA Approaches . . . . . . . . . . . . . . . . . . . . . . . . .			292
11.7	Recombinant DNA Expression Systems . . . . . . . . . . . . . . . . . . . . .			292
	11.7.1 Heterologous Gene Expression in Escherichia coli . . . . . . . . . .			292
	11.7.2	Fungal Expression Systems . . . . . . . . . . . . . . . . . . . . . . . .		293
	11.7.3	Baculovirus Expression Systems . . . . . . . . . . . . . . . . . . . . .		294
	11.7.4 Stable Transformations of Insect Cells . . . . . . . . . . . . . . . . .			295
	11.7.5 Expression Using Mammalian Cells . . . . . . . . . . . . . . . . . . .			295
	11.7.6	Expression Systems: Concluding Remarks . . . . . . . . . . . . . . .		295
11.8	Recombinant DNA Constructs . . . . . . . . . . . . . . . . . . . . . . . . . .			296
	11.8.1	Antibody-based Constructs . . . . . . . . . . . . . . . . . . . . . . .		296
	11.8.2	Receptor-targeted Constructs . . . . . . . . . . . . . . . . . . . . . .		300
		11.8.2.1	Cytotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . .	300
		11.8.2.2	Toxin-targeted Constructs . . . . . . . . . . . . . . . . . . .	300
		11.8.2.3	TfR-directed Constructs . . . . . . . . . . . . . . . . . . . .	301
11.9	Recombinant Domains as Building Blocks for Drug Targeting Constructs . .			302
	11.9.1	Targeting Domain . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		302
	11.9.2	Membrane Translocation Domain . . . . . . . . . . . . . . . . . . . .		303
	11.9.3	Assembly Domain . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		303
11.10	Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .			304
References . .		. . . . .	. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	304
12	Use of Human Tissue Slices in Drug Targeting Research
	Peter Olinga, Geny M. M. Groothuis . . . . . . . . . . . . . . . . . . . . . . .			309
12.1	Introduction . .		. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	309
12.2	Preparation of Liver Slices . . . . . . . . . . . . . . . . . . . . . . . . . . . . .			311
12.3	Incubation and Culture of Liver Slices . . . . . . . . . . . . . . . . . . . . . .			312
	12.3.1	Incubation Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . .		312
	12.3.2 Evaluation of Incubation Systems . . . . . . . . . . . . . . . . . . . .			313
	12.3.3 Incubation Systems for Human Liver Slices . . . . . . . . . . . . . .			316
	12.3.4	Oxygenation and Culture Media for Liver Slice Incubation . . . . .		316
	12.3.5 Pre-incubation of Liver Slices . . . . . . . . . . . . . . . . . . . . . .			317
12.4	Viability and Functionality of Liver Slices . . . . . . . . . . . . . . . . . . . .			317
12.5	In Vitro Transport Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .			318
	12.5.1	Transport in Hepatocytes . . . . . . . . . . . . . . . . . . . . . . . . .		318
	12.5.2 Transport in Liver Slices . . . . . . . . . . . . . . . . . . . . . . . . .			319
12.6	The Use of Liver Slices in Drug Targeting Research . . . . . . . . . . . . . .			321
	12.6.1 Distribution and Transport of Drug Targeting Devices . . . . . . . .			321
12.7	Efficacy Testing of the Drug Targeting Device in the Liver . . . . . . . . . . .			323

	Contents	XXV
12.8.	Tissue Slices from Other Organs . . . . . . . . . . . . . . . . . . . . . . . . .	327
12.9	Summary and Future Possibilities . . . . . . . . . . . . . . . . . . . . . . . . .	327
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		328
13	Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting
	Johannes H. Proost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	333
13.1	Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	333
	13.1.1 Drug Targeting and Effectiveness: The Role of Pharmacokinetics . .	333
	13.1.2 Pro-drugs and Drug–Carrier Conjugates . . . . . . . . . . . . . . . .	334
	13.1.3 Scope of this Chapter . . . . . . . . . . . . . . . . . . . . . . . . . . .	335

13.2Pharmacokinetics and Pharmacodynamics, Modelling, Simulation, and

	Data Analysis .		. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	335
	13.2.1	Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		335
		13.2.1.1	Pharmacokinetic Processes . . . . . . . . . . . . . . . . . .	335
		13.2.1.2	Transport Mechanisms . . . . . . . . . . . . . . . . . . . . .	336
		13.2.1.3	Perfusion and Permeability . . . . . . . . . . . . . . . . . .	336
		13.2.1.4 Plasma Protein Binding and Tissue Binding . . . . . . . . .		337
	13.2.2	Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . .		337
	13.2.3	Model and Modelling . . . . . . . . . . . . . . . . . . . . . . . . . . .		337
	13.2.4	Pharmacokinetic Models . . . . . . . . . . . . . . . . . . . . . . . . .		338
		13.2.4.1	Compartmental Models . . . . . . . . . . . . . . . . . . . .	338
		13.2.4.2	Physiologically-based Pharmacokinetic (PB-PK) Models .	340
		13.2.4.3 Compartmental Models Versus Physiologically-based
			Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	343
		13.2.4.4	Principles of Modelling . . . . . . . . . . . . . . . . . . . .	343
	13.2.5	Pharmacodynamic Models . . . . . . . . . . . . . . . . . . . . . . . .		344
		13.2.5.1	Sigmoid Emax Model . . . . . . . . . . . . . . . . . . . . . .	344
		13.2.5.2	Growth/Kill Models . . . . . . . . . . . . . . . . . . . . . .	344
		13.2.5.3	Empirical PK/PD Relationships . . . . . . . . . . . . . . .	345
	13.2.6	Pharmacokinetic/Pharmacodynamic (PK/PD) Models . . . . . . . .		345
	13.2.7	Simulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		346
	13.2.8	Data Analysis by Modelling . . . . . . . . . . . . . . . . . . . . . . .		346
		13.2.8.1	Model Building . . . . . . . . . . . . . . . . . . . . . . . . .	346
		13.2.8.2 Defining the Objective Function . . . . . . . . . . . . . . .		347
		13.2.8.3 Searching the Best-fitting Set of Parameters . . . . . . . . .		348
		13.2.8.4 Identification of Model Parameters . . . . . . . . . . . . . .		348
		13.2.8.5 Goodness-of-Fit . . . . . . . . . . . . . . . . . . . . . . . . .		349
		13.2.8.6	Model Selection . . . . . . . . . . . . . . . . . . . . . . . .	350
13.3	Pharmacokinetic Models for Drug Targeting . . . . . . . . . . . . . . . . . .			351
	13.3.1 Model of Stella and Himmelstein . . . . . . . . . . . . . . . . . . . .			351
		13.3.1.1	Disposition of DC . . . . . . . . . . . . . . . . . . . . . . .	352
		13.3.1.2 Delivery of the DC to the Target Site . . . . . . . . . . . . .		353

XXVI	Contents
		13.3.1.3 Release or Activation of D at the Target Site . . . . . . . .	353
		13.3.1.4 Removal of D from the Target Site . . . . . . . . . . . . . .	354
		13.3.1.5 Release of D at Non-target Sites . . . . . . . . . . . . . . .	355
		13.3.1.6 Disposition of D . . . . . . . . . . . . . . . . . . . . . . . .	355
	13.3.2	Model of Hunt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	355
	13.3.3	Model of Boddy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	357
	13.3.4 Model of Rowland and McLachlan . . . . . . . . . . . . . . . . . . .		357
13.4	Measures of Effectiveness of Drug Targeting . . . . . . . . . . . . . . . . . .		357
	13.4.1	Therapeutic Availability (TA) . . . . . . . . . . . . . . . . . . . . . .	358
	13.4.2	Drug Targeting Index (DTI) . . . . . . . . . . . . . . . . . . . . . . .	358
	13.4.3	Targeting Index (TI) . . . . . . . . . . . . . . . . . . . . . . . . . . .	359

13.5Evaluation of Effectiveness of Drug Targeting Using PK

	and PK/PD Modelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .		359
	13.5.1 Effectiveness of an Ideal Carrier . . . . . . . . . . . . . . . . . . . . .		359
	13.5.2 Implications of the DTI Concept . . . . . . . . . . . . . . . . . . . .		361
	13.5.3 Drug Candidates for Effective Targeting . . . . . . . . . . . . . . . .		363
	13.5.4 Limitations of PK and PK/PD Modelling . . . . . . . . . . . . . . . .		363
13.6	Examples of PK Modelling in Drug Targeting . . . . . . . . . . . . . . . . . .		364
	13.6.1	In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	364
	13.6.2	In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	365
	13.6.3	Regional Drug Administration . . . . . . . . . . . . . . . . . . . . . .	365
	13.6.4	Controlled Drug Delivery . . . . . . . . . . . . . . . . . . . . . . . .	366
	13.6.5	Pharmacokinetic Properties of Macromolecular Carrier Systems . .	366
13.7	Software for PK and PK/PD Modelling . . . . . . . . . . . . . . . . . . . . .		366
13.8	Perspectives and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . .		367
References . .		. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	368

14Drug Targeting Strategy:

Scrutinize the Concepts Before Screening the Constructs

	Dirk K. F. Meijer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	371
14.1	Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	371
14.2	Receptor-based drug targeting . . . . . . . . . . . . . . . . . . . . . . . . . .	372
14.3	Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	374

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

377

Drug Targeting Organ-Specific Strategies. Edited by G. Molema, D. K. F. Meijer Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-29989-0 (Hardcover); 3-527-60006-X (Electronic)

Abbreviations and Acronyms

Aco	aconitylated (Chapter 4); aconitic acid (Chapter 11)
cis-Aco	cis-aconitic acid
ACE	angiotensin-converting enzyme
AD	Alzheimer’s disease
ADCC	antibody dependent cellular cytotoxicity
ADEPT	antibody-directed enzyme pro-drug therapy
ADP	adenosine diphosphate
AEA	polyvinylacetal diethylaminoacetate
AIA	antigen-induced arthritis
ALL	acute lymphoblastic leukaemia
AML	acute myeloid leukaemia
ALT	alanine transaminase
AMP	adenosine monophosphate
ANP	atrial natriuretic peptide
AOX	alcohol oxidase (promoter)
AP	alkaline phosphatase
AP-1	activator protein-1
APL	acylated poly lysine
APP	amyloid precursor protein
APC	antigen presenting cell
APS	aerodynamic particle sizer
AS-ODN	antisense oligodeoxynucleotide
AST	aspartate transaminase
ATP	adenosine triphosphate
AUC	area under the (plasma concentration-time) curve
AVP	arginine vasopressin
AZTMP	azidothymidine-monophosphate
BBB	blood-brain barrier
B-CSF-B	blood-cerebrospinal fluid barrier
BDL	bile duct ligation
BDNF	brain derived neurotrophic factor
BDO	bile duct occlusion
BMEC	bovine microvessel endothelial cell
BSA	bovine serum albumin

XXVIII Abbreviations and Acronyms

Bs(M)Ab	bispecific (monoclonal) antibody
BUI	brain uptake index
C	proportionality constant (Chapter 3); complement (Chapter 8);
	(drug) carrier, any part of a drug-carrier conjugate which is not
	the pharmacologically active moiety (Chapter 13)
Cp	plasma concentration
Css	drug concentration at steady state
CT	tissue concentration
CAM	chick chorio-allantoic membrane assay
CAT	catalase; chloramphenicol acetyl transferase (Chapter 3)
CBF	cerebral blood flow
CCA	cell cycle arrest
CD	cluster of differentiation
CDR	complementary determining region
CEA	carcinoembryonic antigen
CFC	chlorofluorocarbon
cfu	colony-forming units
CHO	Chinese hamster ovary cells
CL	clearance
CLuptake,app	apparent clearance uptake
CLuptake	clearance uptake
CLL	chronic lymphoblastic leukaemia
CMV	cytomegalovirus
CNS	central nervous system
COER	controlled onset extended release
COPD	chronic obstructive pulmonary disease
COS	African green monkey kidney cells
COX	cyclooxygenase
CPG2	pseudomonas carboxypeptidase-2
CSF	cerebrospinal fluid
CTDC	colon-targeted delivery capsule
CTL	cytotoxic T lymphocyte
CTLA-4	cytotoxic T lymphocyte associated protein-4
CVO	circumventricular organ
D	(active, free) drug, active form of the drug, not bound to drug
	carrier
DA	aerodynamic particle diameter
DE	equivalent volume diameter
DAB	diphtheria toxin enzymatic A domain and binding B
	domain
DC	dendritic cell (Chapter 1); drug-carrier conjugate, the conjugate
	of a drug and a drug carrier (Chapter 13)
DDI	drug delivery index

	Abbreviations and Acronyms XXIX
Dexa	dexamethasone
DIVEMA	divinyl ether and maleic anhydride copolymer
DOC system	dynamic organ culture system
DPI	dry powder inhaler
DSS	dextran sodium sulphate
DT	diphtheria toxin
DTH	delayed-type hypersensitivity
DTI	drug targeting index
DTPA	diethylenetriaminepenta acid
EC	energy charge
ECM	extracellular matrix
EF	edema factor
EF-2	elongation factor-2
EGF	epidermal growth factor
EGP-2	epithelial glycoprotein-2
ELISA	enzyme-linked immunosorbent assay
EMSA	electric mobility shift assay
EPOR	erythropoietin receptor
fp	plasma unbound fraction
Fab’	antibody fragment with antigen binding capacity
F(ab’)2	antibody fragment consisting of two Fab’
FACS	fluorescent activated cell sorting
FBP	folate-binding protein
FEV1	forced expiratory volume in 1 s
(a/b)FGF	(acidic/basic)fibroblast growth factor (is FGF-1/-2)
FIR	flow increase rate
Form	formaldehyde-treated
FPF	fine particle fraction
Fu(A)	function of the cross section of a flow constriction
Gal	galactose
GDNF	glial cell-line derived neurotrophic factor
GFP	green fluorescent protein
GFR	glomerular filtration rate
GGT	γ-glutamyl transpeptidase
GI	gastrointestinal
Glc	glucose
Gludopa	γ-glutamyl pro-drug of l-dopa
GOX	glucose oxidase
gp	glycoprotein
GR	glucocorticoid receptor
GRE	glucocorticoid responsive element
GRO	growth related protein

XXX Abbreviations and Acronyms

GSH	glutathione
γ-GTP	γ-glutamyl transpeptidase
HAMA	human anti-mouse antibody
HDL	high-density lipoprotein
HDMEC	human dermal microvascular endothelial cell
HFA	hydrofluoroalkane
HGF	hepatocyte growth factor
HIV	human immunodeficiency virus
HPMA	N(-2-hydroxypropyl)methacrylamide
HRP	horseradish peroxidase
HSA	human serum albumin
HSC	hepatic stellate cell
HUVEC	human umbilical vein endothelial cell
IBD	inflammatory bowel disease
ICAM	intercellular adhesion molecule
i.c.v.	intracerebroventricular
IFN	interferon
IGFII/M6P	insulin-like growth factor II/mannose-6-phosphate receptor
IgG	immunoglobulin
IgSF	immunoglobulin superfamily
IκB	inhibitory factor κB
IKK	IκB-kinase
IL	interleukin
IP-10	interferon γ-inducible protein 10
IPTG	isopropyl-β-D-thiogalactopyranoside
IT	immunotoxin
JAB	JAK binding protein
JAK	janus kinase
KC	Kupffer cell
km	Michaelis-Menten constant of transport
LACHSA	lactosylated HSA
LAK	lymphokine activated killer cells
LAT	large neutral amino acid transporter
LDH	lactate dehydrogenase
(ox)LDL	(oxidized) low-density lipoprotein
LF	lethal factor
LH-RH	luteinizing hormone releasing hormone
LMWP	low molecular weight protein
LPS	lipopolysaccharide
LU	lucigenin

	Abbreviations and Acronyms XXXI
LRP	lung resistance related protein
LT	leukotriene
LZM	lysozyme
mAb/MAb	monoclonal antibody
MACS	magnetic activated cell sorting
Mal	maleylated (Chapter 4); maleic acid (Chapter 11)
Man	mannosylated (Chapter 4); mannose (Chapter 5)
MARCO	macrophage receptor with collagenous structure
MBP	maltose binding protein
MCP(-1)	monocyte chemotactic protein(-1)
(p)MDI	(pressurized) metered dose inhaler
MDR	multi-drug resistance
MHC	major histocompatibility complex
MIP	maximal inspiratory pressure (Chapter 3); macrophage inflam-
	matory protein (–1α/β)
MLV-MTP-PE	multilamellar vesicles-muramyl tripeptide-phosphatidyletha-
	nolamine
MMAD	mass median aerodynamic diameter
MMP	matrix metalloproteinase
MPEG	monomethoxypolyethyleneglycol
MPTP	1-methyl-4-phenylpyridinium
MRP	multi-drug resistance related protein
MSLI	multi stage liquid impinger
MTT	3[4,5-dimethyl-thiazole-2-yl]-2,5-diphenyltetrazolium bromide
MUC-1	mucin 1
Nap	naproxen
Na/Pi-2 co-transporter	sodium/phosphate co-transporter
NBD	4-nitrobenz-2-oxa-1,3-diazole
NCE	new chemical entity
NCS	neocarzinostatin
NFκB	nuclear factor κB
NGF	nerve growth factor
NHL	non-Hodgkin’s lymphoma
NIK	NFκB-inducible kinase
NK	natural killer cell
NLA	neutral avidin
NLS	nuclear localization sequence
NO	nitric oxide
NOx	nitrite and nitrate
iNOS	inducible NO synthase
NSAID	non steroidal anti-inflammatory drug

ODN	oligodeoxynucleotide

XXXII Abbreviations and Acronyms

OROS-CT	oral osmotic system for colon targeting
OX26-NLA/SA	conjugate of anti-transferrin receptor antibody OX26 and
	neutral avidin/streptavidin
PA	protective antigen
PAF	platelet activating factor
PB-PK	physiologically-based pharmacokinetic (modelling/models)
PBC	primary biliary cirrhosis
PBMC	peripheral blood mononuclear cell
PC	parenchymal cell/hepatocyte
PCNA	proliferating cell nuclear antigen
PD	Parkinson’s disease (Chapter 2); pharmacodynamics (Chapter
	13)
PDGF	platelet-derived growth factor
PDTC	pyrrolidine dithiocarbamate
PE(40)	Pseudomonas exotoxin (amino acid 1–40)
PECAM	platelet endothelial cell adhesion molecule
PEF	peak expiratory flow rate
PEG	polyethylene glycol
PET	positron emission tomography
PG(E2)	prostaglandin (E2)
PGA	poly-glutamic acid
P-gp	P-glycoprotein
PIFR	peak inspiratory flow rate
PK	pharmacokinetics
PKC	protein kinase C
PK/PD	pharmacokinetic/pharmacodynamic
PMN	polymorphonuclear cell
pro-drug	inactive form of the drug, which is converted within the body to
	the active drug
PS	phosphatidylserine
PS-product	permeability surface area product
PSC	primary sclerosing cholangitis
Qr	renal plasma flow rate
RE	external resistance (to airflow)
RI	internal resistance (to airflow)
RTOT	total resistance (to airflow)
RA	rheumatoid arthritis
RANTES	regulated upon activation, normal T-cell expressed and secreted
RB	Rhodamine B
Re	Reynolds number
RES	reticuloendothelial system
RGD	Arg-Gly-Asp