Chemical Structure of Atorvastatin

1
Chemical Structure of Atorvastatin
2
Cholesterol Biosynthesis Pathway
HMG-CoA reductase
Dolichol
Acetyl CoA
HMG- CoA
Farnesyl pyrophosphate
Mevalonate
Squalene
Cholesterol
Ras protein
Farnesyl- transferase
E,E,E-Geranylgeranyl pyrophosphate
Farnesylated proteins
Geranylgeranylated proteins
Ubiquinones
Data on file, Parke-Davis.
3
Overview of Lipoprotein Metabolism
Exogenous pathway Chylomicron transport of
dietaryfat and cholesterol
Endogenous pathway VLDL and HDL metabolismin
plasma
Dietaryfat andcholesterol
Bileacidscholesterol
LDL CE
B-100
LDL receptor
LDL receptor
Extrahepatic tissues
Liver
Intestine
Remnantreceptor
HDL receptor (?)
Plasma LCAT IDL
HDLreceptor
Remnant CEgtTG
VLDL TGgtCE
Chylomicron TGgtCE
IDL CEgtTG
HDL
A-1
E
A-2
B-100
E
E
B-48
E
B-100
C
C
B-48
LPL
LPL
FFA
FFA
Adipose tissue and muscle
Adipose tissue and muscle
4
HMG-CoA reductase inhibition
Atorvastatin inhibits HMG-CoA reductase
Reduced cholesterol synthesis
Upregulation of LDL receptors
Decreased VLDL production
Increased removal and catabolism of LDL
Less VLDL available for conversion to LDL
Decreased TC, LDL-C, and TG
5
Pharmacokinetics of Atorvastatin

• Mean plasma elimination half-life, 14 hours
• Half-life is independent of dose
• No effect of renal impairment on drug levels or
  lipidresponse no dose adjustment necessary
• Can be taken at any time, day or night
• No food effect demonstrated

6
Atorvastatin Effects on the Arterial Wall
Mechanisms in yellow are known to be positively
affected by atorvastatin
Monocyte adherence
HDL
Platelet aggregation
LDL
BLOOD
ENDOTHELIUM
Foam cell
Nitric oxide (Endothelial function)
CE
CE
LDL
CE
Oxidation
Macrophage
N
CE
Activation (MMP)
N
Ox-LDL
MATRIX
Smooth muscle cells (proliferation and migration)
The clinical relevance of these effects has not
been established. Data on file, Parke-Davis.
7
Effect of Atorvastatin on Atherosclerotic Lesion
Development

Plt0.05 vs progression control. Lesion
development was assessed in the thoracic aorta of
8 hypercholesterolemic New Zealand White rabbits
fed with statin for 8 weeks. The clinical
relevance of these results has not been
established. This does not represent a licensed
use of atorvastatin. Bocan TM et al.
Atherosclerosis 199411127142.
8
Effect of Atorvastatin on Atherosclerotic Lesion
Size
Iliac-femoral cross-sectionallesion area (mm2
mean SEM)

Plt0.05 vs progression control. Lesion size was
assessed in the iliac-femoral artery of 8
hypercholesterolemic New Zealand White rabbits
fed with statin for 8 weeks. The clinical
relevance of these results has not been
established. This does not represent a licensed
use of atorvastatin. Bocan TM et al.
Atherosclerosis 199411127142.
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Effect of Atorvastatin on Hemorheological and
Hemostatic Parameters
Plasma viscosity
AA-induced platelet aggregation
Factor VII activity
RBC sedimentation




Plt0.05 vs baseline. AA arachidonic acid RBC
red blood cell. Hemorheologic and hemostatic
parameters measured in 22 hyperlipidemic patients
after 12 weeks of treatment with atorvastatin 80
mg/day. The clinical relevance of these results
has not been established. This does not represent
a licensed use of atorvastatin. Dujovne CA et
al. Presented at the 66th European
Atherosclerosis Society Congress, 13?17 July
1996, Florence, Italy.
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Atorvastatin Inhibits Smooth Muscle Cell
Proliferation and Migration in Culture
Proliferation in monoculture(IC50 µM)
Proliferation/migration coculture(IC50 µM)
Human aortic smooth muscle cell (SMC) and
endothelial cell growth was assessed in
monoculture after 5 days using a BrdU-ELISA.In
transfilter cocultures, human aortic SMCs were
growth-stimulated by cocultured human aortic
endothelial cells and 200 µg/ml LDL. SMCs were
counted on day 14 as an index of proliferation
and migration. The clinical relevance of these
results has not been established. This does not
represent a licensed use of atorvastatin. Axel
DI et al. Eur Heart J 199718370.
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Atorvastatin Decreases Monocyte Adhesion Induced
by Modified LDL
Data show monocyte-endothelial adhesion in
response to 250µg/ml oxidised or gyoxidatinely
modified LDL.Pravastatin had no effect on
monocyte adhesion. The clinical relevance of
these results has not been established. This does
not represent a licensed use of
atorvastatin. Harper CM and Fyfe AI. Circulation
199796177.
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Atorvastatin Metabolites Protect Against
Macrophage-Induced LDL Oxidation
Atorvastatin
Para-hydroxy
A. CuSO4
Ortho-hydroxy
Atorvastatin
Para-hydroxy
B. AAPH
Ortho-hydroxy
LDL oxidation (nmol MDA/mg LDL protein)
Atorvastatin
Para-hydroxy
C. Macrophages
Ortho-hydroxy
Drug concentration (µM)
LDL was obtained from five normolipidemic
individuals and was incubated in all three
oxidative systems with increasing concentration
of the drug or its metabolites for 4h at 37C in
systems A and B and for 20h with the cells
(C). The clinical relevance of these results has
not been established. This does not represent a
licensed use of atorvastatin. Aviram M et al.
Atherosclerosis 1998138271?280.