Drug Targeting Organ-Specific Strategies

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QC QR QT QE RC central compartment RR response (target) compartment RT toxicity compartment RE elimination compartment CLR CLT CLE 13.3 Pharmacokinetic Models for Drug Targeting 355 Figure 13.4. Model of Hunt, adapted from reference [6] (Section 13.3.2). The model describes the fate of the active drug (D) only. It consists of four compartments: A central compartment (V C) representing blood and all other tissues not accounted for by the other three compartments, a response (target) compartment (V R) representing all tissues containing target sites for the desired response, a toxicity compartment (V T) representing tissues where the cascade of events leading to a toxic response is initiated, and an elimination compartment (V E) representing the eliminating organs, excluding the elimination sites in the response and toxicity compartments. Each compartment is characterized by a volume of distribution V, a blood flow Q (where Q C = Q R +Q T + Q E), and, except for the central compartment, an elimination clearance CL. Drug delivery is designated by input functions R in the four compartments. Drug targeting and conventional drug administration are modelled by changing the relative contributions of R C, R R, R T, and R E. When R C = R T = R E = 0, the drug carrier is an ideal targetspecific carrier. drug effect after the conclusion of drug administration.To evaluate the time course of action, a full model, including the pharmacokinetic behaviour of the drug–carrier conjugate, should be used, for example the model of Stella and Himmelstein (Section 13.3.1) or the model of Boddy et al. (Section 13.3.3).
356 13 Pharmacokinetic/Pharmacodynamic Modelling in Drug Targeting Boddy and Aarons [44] used a simplified model, in which the toxicity sites are included in the systemic (non-target) tissues to allow derivation of the Drug Targeting Index which was less restricted by model assumptions.Their approach was criticized by Siegel et al. [45]. When some drug release from the carrier occurs at either the central, toxicity or elimination regions, the DTI is affected by the specific fraction of the drug delivered to each region. Since these regions are combined by Boddy and Aarons into a single systemic region, their model cannot account for this effect. Siegel et al. came to the conclusion that the model of Hunt et al. and the model of Boddy and Aarons are only equivalent in the case of an ideal carrier. RC(DC) CLC(DC) DC response (target) compartment VR QCR DC central compartment VC QCT DC toxicity compartment VT kR kC kT D response (target) compartment VR QCR D central compartment VC QCT D toxicity compartment VT CLR (D) RC(D) CLC (D) CLT (D) Figure 13.5. Model of Boddy, adapted from reference [7] (Section 13.3.3). The drug–carrier conjugate (DC) is administered at a rate R C(DC) into the central compartment, which is characterized by a volume of distribution V C. DC is transported by blood flow Q CR to and from the response (target) compartment, characterized by a volume of distribution V R, and by blood flow Q CT to and from the toxicity compartment, characterized by a volume of distribution V T. DC is eliminated from only the central compartment with a clearance CL C(DC). The active drug (D) is released from DC in the central, response and toxicity compartments with first-order rate constants k C, k R and k T, respectively. The D is distributed over these compartments in a manner similar to the DC. The D is eliminated from these compartments with a clearance of CL C(D), CL R(D) and CL T(D), respectively. Conventional drug administration can be simulated by the input of D at a rate R C(D) into the central compartment.
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Drug Targeting Organ-Specific Strat
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Preface Drug Targeting Organ-Specif
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Foreword Drug Targeting Organ-Speci
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X List of Contributors Henderik W.
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XII List of Contributors Grietje Mo
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Contents Drug Targeting Organ-Speci
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Contents XVII 3 Pulmonary Drug Deli
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Contents XIX 5.2.1.6 Identification
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Contents XXI 7.5 In Vitro Technique
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Contents XXIII 9.4 Tumour Vasculatu
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Contents XXV 12.8. Tissue Slices fr
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Dexa dexamethasone DIVEMA divinyl e
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LRP lung resistance related protein
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ROS reactive oxygen species RSV res
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Index a ADEPT 217, 224, 268, 291 ad
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e E. coli expression system 292 eff
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polymers, soluble 4, 218 - dendrime
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2 1 Drug Targeting: Basic Concepts
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24 2 Brain-Specific Drug Targeting
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54 3 Pulmonary Drug Delivery: Deliv
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4 Cell Specific Delivery of Anti-In
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The sinusoids are lined by the disc
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4.2.2.2 Phagocytosis and Transcytos
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ther inflammatory cells or accessor
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4.3 Hepatic Inflammation and Fibros
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process is not yet available. Sever
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this carrier to the KCs.When the ma
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e taken up rapidly by mannose recep
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y the transcriptional regulatory pr
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4.8 Testing Liver Targeting Prepara
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4.8 Testing Liver Targeting Prepara
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4.9 Targeting of Anti-inflammatory
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4.9 Targeting of Anti-inflammatory
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with monoclonal and bispecific anti
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References 117 [50] Coleman DL, Eur
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References 119 [133] Cronstein BN,
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5 Delivery of Drugs and Antisense O
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5.1 Introduction 123 convoluted tub
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treatment of the targeted cell and
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CL uptake (ml/min/g) centration pro
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5.2.1.4 Specific Binding of Alkylgl
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5.2 Renal Delivery Using Pro-Drugs
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5.2 Renal Delivery Using Pro-Drugs
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5.3 Renal Delivery Using Macromolec
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5.4 Renal Delivary of Antisense Oli
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5.4 Renal Delivery of Antisense Oli
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5.4.8 Benefits and Limitations of A
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via reabsorption from the luminal s
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References 153 [66] Franssen EJF, M
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References 155 [145] Van Zwieten PA
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158 6 A Practical Approach in the D
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172 7 Vascular Endothelium in Infla
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8 Strategies for Specific Drug Targ
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8.2.2 Histogenesis The traditional
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may become obstructed and compresse
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8.5 Strategies to Deliver Drugs to
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8.5 Strategies to Deliver Drugs to
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larly cytotoxic immune effector cel
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contributes to limited tumour penet
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ples onto anti-EGP-2 scFv. Biologic
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In the case of drug-monoclonal anti
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cells, the presence of co-stimulato
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Monomethoxy-polyethylene glycol CH
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e efficiently loaded into the lipos
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8.6 Clinical Studies 223 Table 8.5.
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8.6.3 (Synthetic) (co)Polymers Solu
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8.8 Conclusions and Future Perspect
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References 229 [43] Chaouchi NA, Va
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References 231 [126] Czuczman MS, G
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234 9 Tumour Vasculature Targeting
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256 10 Phage Display Technology for
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11 Development of Proteinaceous Dru
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carrier is an homogenous product. I
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11.3 The Homing Device 11.3 The Hom
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malian cell lines that have acquire
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jugates for the delivery of other a
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11.5 The Linkage Between Drug and C
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actions are directed towards these
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11.5 The Linkage Between Drug and C
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homing potential if the antigen rec
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ly used promoters include T7 RNA po
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the baculovirus expression vector,
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11.8 Recombinant DNA Constructs 297
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11.8 Recombinant DNA Constructs 299
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toxic activity. Anthrax and tetanus
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Drug Targeting Organ-Specific Strategies

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