Pharmaco kinetics

1. Pharmacokinetics of Nanoparticle
(Nanokinetics)
ADME
Administration, Distribution, Metabolism, Excretion
• Chemical composition
• Structural diversity
• Surface modifications
• Particle size
• Relevant routes of exposure
• Transport across barrier (Placenta, skin, GI, BBB)
• Tissue selectivity
• Metabolism
• Excretion

2. Hurdles
• Interaction of NP with plasma proteins,
coagulation factors, platelets, red and white
blood cells.
• Cellular uptake by diffusion, channels or
adhesive interactions and transmembrane active
processes.
• Binding to plasma components relevant for
distribution and excretion of NP.

3. Factors affecting
pharmacokinetics

4. Chemical composition
Nanoscale materials may possess unexpected
physical, chemical, optical, electrical and
mechanical properties, different from their
macrosized counterparts.

5. Organic nanoSpatrrtiuclcestural diversity
liposomes dendrimers carbon nanotubes
Inorganic nanoparticles
quantum dots magnetic NPs gold NPs

6. Surface modifications
PEGylated NP in “Brush ”
configuration attract less
Opsonins from plasma
Monuclear phagocyte system (MPS) is the major contributor for the clearance of
nanoparticles. Reducing the rate of MPS uptake by minimizing the opsonization
is the best strategy for prolonging the circulation of nanoparticles..

7. • opsonization
• NP is marked for ingestion and
destruction by phagocytes.
Opsonization involves the binding of
an opsonin. After opsonin binds to the
membrane, phagocytes are attracted.

10. poloxamine
PEG
GANGLIOSIDE

11. PLGA versus PEG-PLGA
Liu et al.

12. Particle size
Arruebo M. et al. Nanotoday 2, 2007
NPs endowed with specific characteristics: size, way of conjugating the drug
(attached, adsorbed, encapsulated), surface chemistry, hydrophilicity/hydrophobicity,
surface functionalization, biodegradability, and physical response properties
(temperature, pH, electric charge, light, sound, magnetism).

13. Renal
elimination
Elimination by RES
(Reticuloendothelial system)
Spleen opsonization
100 cut-off
<5.5 200-250 nm
Optimal NP size

14. Liver, Spleen, Lung

15. Routes of exposure
• Inhalation
• Absorption via the olfactory nervous system
• Oral administration
• Dermal absorption
• Systemic administration

17. Inhalation exposure
• Distribution of inhalated NP was observed in
animal models, but not confirmed in human.

18. Inhalation exposure
• Particle deposition depends on particle size,
breathing force and the structure of the lungs.
• Brownian diffusion is also involved resulting in
the deep penetration of NP in the lungs and
diffusion in the alveolar region.
• NP >100 nm may be localized in the upper
airways before the transportation in the deep
lung.

19. Inhalation exposure

20. Absorption via the olfactory nervous system
• This is an alternative port of entry of NP via
olfactory nerve into the brain which circunventes
the BBB.
• Neuronal absorption depends on chemical
composition, size and charge of NP.

22. Absorption via the olfactory nervous
system
Surface enginnering of nanoparticles with lectins opened a
novel pathway to improve the brain uptake of agents
loaded by biodegradable PEG-PLA nanoparticles following
intranasal administration. Ulex europeus agglutinin I (UEA
I), specifically binding to L-fucose, which is largely located
in the olfactory epithelium was selected as ligand and
conjugated onto PEG-PLA nanoparticles surface.

23. Absorption via the olfactory nervous system
OLFACTORY BULB OLFACTORY TRACT
CEREBRUM CEREBELLUM
BLOOD

24. Oral absorption
• Gastrointestinal tract represents an important port of
entry of NP. The size and shape and the charge of NP
are critical for the passage into lymphatic and blood
circulation.
• 50 nm – 20 μm NP are generally absorbed through
Peyer’s patches of the small intestine
• NP must be stable to acidic pH and resistant to protease
action. Polymeric NP (e.g. PLGA ,polylactic-co-glycolic,
and SLN
• Small NP < 100 nm are more efficiently absorbed
• Positively charged NP are more effectively absorbed
than neutral or negatively charged ones.

26. 26
Oral route
• Nature’s intended mode of
uptake of foreign material
• most convenient
• preferred route of
administration
• No pain (compared to
injections)
• Sterility not required
• Fewer regulatory issues
Nano-Systems
 Direct uptake through the
intestine
 Protection of encapsulated
drug
 Slow and controlled release
 Can aid delivery of drugs
with various
pharmacological and
physicochemical properties

27. 27
Lymphatic uptake of nanoparticles
Liver
NP
Blood vessel
Systemic circulation
PPs
Intestinal lumen
(II) (l)
(lll)
Mechanism of uptake of orally administered nanoparticles. NP: Nanoparticles
PPs: Peyers patches, (l) M-cells of the Peyer’s patches, (ll) Enterocytes, (lll)
Gut associated lymphoid tissue (GALT)
Bhardwaj et, al. Pharmaceutical Aspects of Polymeric Nanoparticles for Oral Delivery, Journal of Biomedical Nanotechnology (2005), 1, 1-23

28. Distribution following oral absorption

29. Distribution following oral exposure
•Solid lipid nanoparticles (SLN).
•Wheat germ agglutinin-N-glutaryl-phosphatylethanolamine
(WGA-modified
SLN).
•WGA binds selectively to
intestinal cells lines.

30. Dermal absorption
• Dermal absorption is an important route for
vaccines and drug delivery.
• Size, shape, charge and material are critical
determinants for skin penetration.
• Negatively charged and small NP (<100nm)
cross more actively the epidermis than neutral or
positively charged ones.

34. Dermal absorption

35. Distribution following intravenous exposure
• NP kinetics depends on size charge and
functional coating.
• Delivery to RES tissues: liver, spleen, lungs and
bone marrow.

36. Distribution following intravenous exposure
3,5
3
2,5
2
1,5
1
0,5
0
0 2 4 6 8 10 12
Fluorescence Intensity
Free Cholesteryl Bodipy
urine
blood
Cholesteryl Bodipy-liposomes
3,5
3
2,5
2
1,5
1
0,5
0
0 2 4 6 8 10 12
urine
blood
spleen
Fluorescence Intensity
Time-course of biodistribution of
Cholesteryl Bodipy injected i.v. in
healthy rats (157 mg/rat).
Roveda et al., 1996

39. Metabolism
Inert NP are not metabolized (gold and silver,
fullerenes, carbon nanotubes).
Functionalized or “biocompatible” NP can be
metabolized effectively by enzymes in the body,
especially present in liver and kidney.
The intracellularly released drug is metabolized
according to the usual pathways.

40. POLYMERIC NANOPARTICLES
•Hydrolysis of ester bond; degradation products
alkylalcohol and poly(cyanoacrylic acid) are
eliminated by kidney filtration

41. GOLD NP
studies from the literature show that very little
gold is excreted from the body following
intravenous (i.v.) administration of gold
nanoparticles with a hydrodynamic (HD)
diameter exceeding 8 nm. This is in part a
consequence of the gold nanoparticles not
being composed of subunits that can be easily
broken down.

42. LIPOSOMES
are completely degraded
Phospholipids and cholesterol
follow lipid catabolic pathways
Fatty acids are oxidised
Cholesterol is degraded into bile
acids

43. Excretion
Data are not available regarding the accumulation
of NP in vivo.
The elimination route of absorbed NP remained
largely unknown and it is possible that not all
particles will be eliminated from the body.
Accumulation can take place at several sites in
the body. At low concentrations or single
exposure the accumulation may not be
significant, however high or long-term exposure
may play a relevant role in the therapeutical
effects of the active ingredient.

44. Mechanisms of Removal from Circulation
• Fast removal from circulation
-binding to cells, membranes, or plasma proteins
-uptake by phagocytes (macrophages)
-trapping in capillary bed (lungs)
• Renal clearance
-size restriction for kidney glomerulus is ~30-35 kDa for polymers
(~20-30 nm)
• Extravasation
-depends on the permeability of blood vessels
the primary route of excretion for nanoparticles greater than 8 nm is
through the hepatobiliary system in which the particles may be excreted
into bile by hepatocytes and eliminated in feces
. Additionally, nanoparticles may be phagocytosed by Kupffer cells of the
reticuloendothelial system (RES), and if not broken down by intercellular
processes, will remain in this body location long-term.2, 3 and 9

45. Excretion

48. Devalapally H., J.Pharm.Sci. 9966::22554477--22556655,, 22000077

49. Defining dose for NP in vitro
• Particles are assumed to be spherical, or can be represented as spheres,
• d is the particle diameter in cm,
• surface area concentration is in cm2/ml media,
• mass concentration is in g/ml media,
• # indicates particle number, and particle density is in g/cm3.