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TABLE 4.5 ADME Phenomena and the Tools for their Evaluation
Tool Absorption Distribution Metabolism Renal Excretion Biliary Excretion
In vivo
.
PO administration
.
Tissue distribution
.
Mass balance
.
Mass balance
.
Mass balance
.
ID administration
.
QWBA
.
Portal vein dosing
.
Urine collection
.
Bile cannulated
animals
.
Portal vein sampling
.
MALDI
.
KO animals
.
Transgenic/
humanized mice
.
Formulation
.
Microdialysis
.
Humanized animals
.
Food effect
.
KO mice
.
Chemical inhibitors
.
KO animals
.
Chemical inhibitors
.
Allometric scaling
.
Humanized animals.Chemical inhibitors
.
In situ intestinal
perfusion
In situ
.
Isolated intestinal
.
Isolated organ
.
Isolated liver
.
Isolated kidney
.
Isolated liver
Ex vivo and in vitro—
species specific
.
Intestinal sections
.
Tissue/plasma protein
binding
.
Intestinal sections
.
Kidney slices
.
Sandwiched
hepatocytes
.
Inverted intestinal
sacs
.
BBB/tissue
permeability models
.
Liver slices
.
Transfected cells
.
Transfected cells
.
Cell monolayers
.
Hepatocytes
.
Hepatocytes
.
Sandwiched
hepatocytes
.
Transfected cells
.
Microsomes
.
Membrane vesicles
.
S9
.
Artificial membranes
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In vitro—nonspecies
specific
.
Albumin-
immobilized
columns
.
Recombinant
enzymes
.
Physicochemical
properties
.
Physicochemical
properties
.
Physicochemical
properties
.
Artificial membranes
.
Physicochemical
properties
.
Dissolution/solubility
.
Physicochemical
properties
In silico
.
Physicochemical
properties
.
Volume
.
Clearance
.
Renal clearance
.
Biliary clearance
.
Permeability
.
Protein binding
.
Sites of metabolism
.
Solubility
.
PK profile
.
Half-life
.
Absorption profile
.
Transporter SAR
.
Inhibition/induction
.
MAD
.
BBB uptake
.
Transporter SAR
.
Transporter SAR
.
MDR1
.
Allometric scaling
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preclinical safety findings usually in multiple day in vivo toxicology screens in both
rodent and nonrodent species. Plasma protein binding data should be available in
efficacy models, safety species, and human so that unbound drug concentrations and
multiples can be compared. A more detailed ADME evaluation of selected final
dosage form of the com pound that is expected to be used for initial regulated
toxicology studies and human dosing is conducted in several animal species including
rodents and nonrodents.
As part of an early risk assessment, some mechanistic DDI studies may be
conducted in human cell systems in vitro. Early comparisons of the metabolism of
drug candidates in both in vitro human syst ems and in vitro and in vivo animal models
are conducted to ensure the absence of unique human metabolites not present in
animal species used for safety evaluation.
A significant number of additional studies are usually performed to support further
development of a drug candidate and include more definitive radiolabeled ADME
studies to assess metabolite profiles in humans and toxicology species, a broader
safety evaluation of the drug candidate (e.g., longer term toxicology, reproductive
toxicology, carcinogenicity, and juvenile toxicology), and special studies to address
some specific issue of clinical development (e.g., metabolite safety, mechanistic
understanding of an unexpected clinical finding).
4.7 TOOL SUMMARY FOR ASSESSING ADME PROPERTIES
The various ADME tools discussed in this chapter are provided as a quick reference
(Table 4.5).
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