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The Effects of Hyperlipidemia on the Pharmacokinetic and
Pharmacodynamic Aspects of KetoconazoleSupervisor: Dr. Dion Brocks
PhD Student : Dalia Hamdy El Sayed(2005/2010)
HyperlipidemiaDefinition:
An elevation of one or more lipids including cholesterol, cholesterol esters, phospholipids and triglycerides in the bloodstream
Causes:genetic effect
diet drugs diseases
2
3
becoming an increasing risk with the ongoing increase in obesity world wide.
Hyperlipidemia
Centre of Disease Control, 2004
Adults age ≥ 20 with high cholesterol serum levels
17%
The packages via which lipid movement is accomplished through the body
classified into:Chylomicrons VLDLLDLHDL
Lipoproteins
4
Apolipoproteins responsible for identification and uptake by lipoprotein receptors
LDL Receptors family: group of cell surface receptors that transport a number of macromolecules into cells through receptor mediated endocytosis LDL Receptors :Highly expressed in Liver & Adrenal glands
Uptake at cellular level
Plasma membrane
Nucleus
Golgi
Chung NS, Adv Drug Deliv Rev. 56(9). 2004 5
VLDL Receptors: Highly expressed in heart , brain, adipose and muscle tissues
Uptake at cellular level
VLDL Chylomicron
LPL
IDL (VLDL remnant) Chylomicron remnant
Free Fatty acids
VLDL receptor
Myocardium
FAT/CD36FATPFABPpmSimple
diffusion
Takahashi S, Mol Cell Biochem. 48(1-2):.2003 6
LPL
LDL
LDL receptor
Hyperlipidemia and PKRecent studies have shown that HL could influence PK of some highly lipophilic drugs.
7
Hyperlipidemia and PKRecent studies have shown that HL could influence PK of some highly lipophilic drugs.
Metabolising enzymes
8
Clearance and volume of distribution
Hyperlipidemia and PKRecent studies have shown that HL could influence PK of some highly lipophilic drugs.
NifedipineAmiodaroneHalofantrineCyclosporine
A
9
10
Hyperlipidemia and PDNifedipine:
trend of decreasing mean arterial pressure
Eliot LA et al.
Unbound plasma concentration
Nephrotoxicity was observed after repeated doses in HL
Aliabadi et al.
Cyclosporine:
Lipop
rote
in-re
cept
or
mediat
ed up
take
of dr
ug
lipop
rote
in co
mplex ?
I. Effect of HL
Ketoconazole
11
Keto
cona
zole
First orally introduced azole antifungal drug.
Chiral drug that is clinically administered as (1:1) racemate of the cis-enantiomers
12
A pair of non superimposable mirror image stereoisomers
Enantiomers??
13
Differ in optical activity ( rotation of plane polarized light)
Have same physicochemical properties May differ in their pharmacokinetics
and pharmacodynamics
Enantiomers??
polarizer observeranalyzer
14
Only one of the two enantiomers shown can achieve three point binding with hypothetical binding site (e.g. an enzyme)
Enantiomers??
15
Mechanism of ActionCYP450 mediated 14-α-
demethylation of lanosterol
Ergosterol biosynthesis(fungi, mammalian tissues)Keto
cona
zole
Pharmacodynamics (-)-KTZ ~ 2 fold more potent CYP3A inhibitor and more
antifungal activity than its antipode
KTZ use has been limited by -serious drug-drug interactions (CYP3A and others) -adverse effects
In drug development, KTZ is used to study the possibility of drug interactions due to its ability to inhibit CYP3A isoforms
Keto
cona
zole
Protein Binding Strongly Bound to plasma proteins > 97%
Log P = 4.74
Lipophilic Drug !!
No information on lipoprotein binding
Keto
cona
zole
Hypothesis
HL can affect pharmacokinetics and pharmacodynamics of KTZ
19
RationaleKTZ is a chiral compound
HypothesisKTZ, possesses stereoselective pharmacokinetics
ObjectiveDetermine the pharmacokinetics of KTZ enantiomers in rat after administration of racemate
20
21
No Stereospecific assay for the quantitation of enantiomers in biological specimen
Problem!!
1ST Stereospecific HPLC Assay in Biological Specimen
Hamdy DA and Brocks DR. Biomed Chromatogr. 2008 May;22(5):542-7. 22
Chiral Column
Ster
eose
lect
ive
PK o
f KTZ
in R
at (+)-KTZ average plasma concentration (Cavg), clearance and volume of distribution was ~2.1, 0.5, 0.6 fold different than (-)-KTZ, respectively
same terminal phase half life
Moderate Extraction ratio 0.30 and 0.60 for the (+)-and (-) enantiomers,respectively.Hamdy DA and Brocks DR. . Chirality . 2008
23
Ster
esel
ectiv
e PK
of K
TZ in
Rat
Hamdy DA and Brocks DR. . Chirality . 2008
(+)-KTZ Cavg is ~2.4 fold higher than (-)-KTZ
Similar absorption rate (t max)
There was no difference between oral bioavailability of both enantiomersThe half life increase with increasing dose
24
The C max and AUC showed disproportional increase with escalating
dose
Ster
eose
lect
ive
PK o
f KTZ
in R
at
Ster
eose
lect
ive
PK o
f KTZ
in R
at
Hamdy DA and Brocks DR. . Chirality . 2008
There was no evidence of stereoselective metabolism in microsomal system.
26
0
1
2
3
4
10mg/L 40mg/L
% u
nbou
nd fr
actio
n
(+)KTZ (-)KTZ
*†
*†Stereoselectivity in protein binding
ConclusionKTZ enantiomers show stereoselective pharmacokinetics
(+)-enantiomer showing higher concentrations and lower clearance which is due to its higher protein binding
KTZ enantiomers showed non linear pharmacokinetics
27
RationaleKTZ is a lipophilic compound
HypothesisKTZ binds to lipoproteins
ObjectiveExamine the influence of hyperlipidemia on in vitro distribution of KTZ enantiomers in rat plasma
28
29KTZ
lipop
rote
in d
istrib
utio
n in
vitr
o
0
10
20
30
40
50
60
70
80
90
100
LPDP TRL LDL HDL
(+)K
TZ P
erce
nt a
ssoc
iatio
n (a
s %
of r
ecov
ered
dru
g)
NL HL
*
*0
10
20
30
40
50
60
70
80
90
100
LPDP TRL LDL HDL
(-)K
TZ P
erce
nt a
ssoc
iatio
n (a
s %
of r
ecov
ered
dru
g)
NL HL
*
†
†
*
(+)-KTZ (-)-KTZ
• In NL plasma LPDP bound > 95% of the KTZ enantiomers
• In HL plasma > 20% of the KTZ recovered in the lipoprotein plasma fractions
Hamdy DA and Brocks DR. AAPS conference . 2008
Conclusion
KTZ binds to lipoproteins
HL changed the pattern by which the lipophilic KTZ enantiomers bind to plasma proteins in vitro
potential change in pharmacokinetics in HL in vivo ??
30
RationaleKTZ binds to lipoproteins
HypothesisHL affects the stereoselective pharmacokinetics of KTZ
ObjectiveExamine the effect of HL on the pharmacokinetics of KTZ enantiomers in rat
31
KTZ PK
(+)-KTZ (-)-KTZ
HL no change in Cavg But higher Vdss
Time (h)
32
0.1
1
10
100
0 2 4 6
(+)-
KTZ
pla
smac
Con
cent
ratio
n (m
g/L)
Time (h)
0.1
1
10
100
0 2 4 6
(-)-K
TZ p
lasm
a co
ncen
tratio
n (m
g/L)
Time (h)
HL
NL
Hamdy DA and Brocks DR. Xenobiotics submitted
KTZ PK Stereoselectivity was changed in HL
rats
33Hamdy DA and Brocks DR. Xenobiotics submitted
Plasma and Liver POHL did not significantly alter drug in liver
34
†Significant difference between liver and plasma AUC in the same lipidemic state (α =0.05)
Hamdy DA and Brocks DR. Xenobiotics submitted
Liver uptake Confirms the trend with
individual time points(-)-KTZ(+)-KTZ
35
0
2
4
6
8
10
12
14
16
18
0 1 2 3 4 5 6
(+)
-KTZ
Kp
Time (h)
NL HL
0
2
4
6
8
10
12
14
16
18
0 1 2 3 4 5 6
(-)-
KTZ
Kp
Time (h)
***
*
Hamdy DA and Brocks DR. Xenobiotics submitted
Conclusion Severe HL caused higher Vss (unable to measure unbound fraction in HL)
Decrease in liver uptake of the (-) enantiomer
Does this affect the inhibitory potency of KTZ on CYP???
36
Rationale(-)KTZ appears to change liver uptake in HL
HypothesisHL can modify the strength of drug-drug interactions involving KTZ
ObjectiveExplore the effect of HL on KTZ-midazolam drug-drug interaction in rat
37
BackgroundMidazolam (MDZ) is:
short acting benzodiazepine, not P-gp substrate
Its clearance and oral bioavailability are primarily governed by CYP3A
used as a probe for measuring CYP3A activity
38
Simultaneous Assay for MDZ and KTZ in Rat Specimen
Hamdy DA and Brocks DR. J. Pharm and Biomed Anal. 2010;53(3):617-22. 39
Simultaneous Assay for MDZ and KTZ in human Specimen
Hamdy DA and Brocks DR. J. Pharm and Biomed Anal. 2010;53(3):617-22. 40
41
KTZ
–MDZ
Dru
g In
tera
ctio
n
10
100
1000
10000
0 1 2 3 4 5 6 7 8 9
Plas
ma
Con
cent
ratio
n (n
g/m
L)
Time (h)
NL MDZ NL MDZ + KTZ
NL MDZ KTZ+MDZ
AUCmg.h/L
2.41±0.597
3.23±0.450
CLL/h
2.17±0.458
1.57±0.200
Fu(%)
1.97±0.38 1.78±0.15
42
KTZ
–MDZ
Dru
g In
tera
ctio
n
10
100
1000
10000
0 1 2 3 4 5 6 7 8 9
Plas
ma
Con
cent
ratio
n (n
g/m
L)
Time (h)
NL MDZ HL MDZ
NL MDZ HL MDZ
AUCmg.h/L
2.41±0.597 2.06±0.338
CLL/h
2.17±0.458 2.48±0.445
Fu(%)
1.97±0.38 0.760±0.29*
43
KTZ
–MDZ
Dru
g In
tera
ctio
n
10
100
1000
10000
0 1 2 3 4 5 6 7 8 9
Plas
ma
Con
cent
ratio
n (n
g/m
L)
Time (h)
NL MDZ NL MDZ + KTZ HL MDZ + KTZ
NL MDZ NL MDZ+KTZ
HL MDZ+KTZ
AUCmg.h/L
2.4±0.59
3.2±0.45 4.8±0.98*
CLL/h
2.2±0.46
1.5±0.20 1.1±0.22*
Fu(%) 1.9±0.38
1.7±0.15 1.0±0.21*
KTZ
–MDZ
Dru
g In
tera
ctio
n
10
100
1000
10000
100000
0 1 2 3 4 5 6 7 8 9 10 11
KT
Z p
lasm
a co
ncen
trat
ion
(ng/
mL
)
Time (h)
NL HL
HL did not affect the KTZ parameters in presence of MDZ
44
Conclusion HL decreased the unbound fraction of MDZ but did not affect its PK
HL decreased liver uptake of KTZ
It potentiates the KTZ-MDZ drug interaction causing higher MDZ Cavg and lower CL
MDZ did not affect the PK of KTZ in NL and HL
45
II. Effect of HL
Amiodarone
46
HL
47
1. Increased AM heart uptake and electrocardiographic changes
2. and HL serum decreased AM metabolism in rat hepatocytes
Future Directions Study the mechanism by which HL affects the uptake of the lipoprotein bound drugs
Investigation of MDZ lipoprotein binding
Effect of HL on the antifungal activity of KTZ
48
Thank You
49
Dr. Dion R. Brocks Dr. Ayman El-Kadi Dr. Fakhreddin Jamali Dr. Kishor Wasan Jackie Fleischer
Lab colleagues
Egyptian ScholarshipDissertation Fellowship