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Effect of Hyperlipidemia on the Pharmacokinetics/Pharmacodynamics of Ketoconazole
1. The Effects of Hyperlipidemia
on the Pharmacokinetic and
Pharmacodynamic Aspects of
Ketoconazole
Supervisor: Dr. Dion Brocks
1
PhD Student : Dalia Hamdy El Sayed
(2005/2010)
2. Hyperlipidemia
Definition:
An elevation of one or more lipids
including cholesterol, cholesterol esters,
phospholipids and triglycerides in the
bloodstream
Causes:
genetic effect
diet
drugs
diseases
2
5. 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
8. Hyperlipidemia and PK
Recent studies have shown that HL could
influence PK of some highly lipophilic
drugs.
Metabolising enzymes
8
Clearance and volume
of distribution
9. Hyperlipidemia and PK
Recent studies have shown that HL could
influence PK of some highly lipophilic
drugs.
Nifedipine
Amiodarone
Halofantrine
Cyclosporine A
9
10. Hyperlipidemia and PD
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:
10
12. Ketoconazole
First orally introduced azole antifungal drug.
Chiral drug that is clinically administered as
(1:1) racemate of the cis-enantiomers
12
16. Mechanism of Action
CYP450 mediated 14-α-
demethylation of lanosterol
Ergosterol biosynthesis
(fungi, mammalian tissues)
Ketoconazole
17. 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
Ketoconazole
22. 1ST Stereospecific HPLC Assay in
Biological Specimen
Hamdy DA and Brocks DR. Biomed Chromatogr. 2008 May;22(5):542-7.
22
Chiral Column
23. StereoselectivePKofKTZinRat
(+)-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
24. StereselectivePKofKTZinRat
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 enantiomers
The half life
increase with
increasing dose
24
25. The C max and AUC
showed disproportional
increase with escalating
dose
StereoselectivePKofKTZinRat
26. StereoselectivePKofKTZinRat
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
%unboundfraction
(+)KTZ (-)KTZ
*†
*†
Stereoselectivity in
protein binding
27. Conclusion
KTZ 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
29. 29
KTZlipoproteindistributioninvitro
0
10
20
30
40
50
60
70
80
90
100
LPDP TRL LDL HDL
(+)KTZPercentassociation(as%ofrecovereddrug)
NL HL
*
*
0
10
20
30
40
50
60
70
80
90
100
LPDP TRL LDL HDL
(-)KTZPercentassociation(as%ofrecovereddrug)
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
30. 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
34. Plasma and Liver PO
HL 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
36. 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
45. 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
47. HL
47
1. Increased AM heart uptake
and electrocardiographic
changes
2. and HL serum decreased AM
metabolism in rat hepatocytes
48. 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
49. Thank You
49
Dr. Dion R. Brocks
Dr. Ayman El-Kadi
Dr. Fakhreddin Jamali
Dr. Kishor Wasan
Jackie Fleischer
Lab colleagues
Egyptian Scholarship
Dissertation Fellowship
Editor's Notes
LP are bound to LP receptors through recognition of apoproteins. Internalization of receptor- LP complex into vesicles takes place. Sorting of LP receptors from LP particles takes place via fusion with endosome. LP receptors are recycled back to cell surface. LDL receptors recognize ApoB100 on LDL. Highly expressed in Liver and Adrenal glands. VLDL receptors recognize Apo C and Apo E on VLDL. Highly expressed in heart, brain, adipose and muscle tissues. Model drug I have been studying is HF.
(2) Receptors contained in vesicles are transported to the cell membrane. (3) LDL receptor expression on the cell surface. (4) Recognition of LDL particle by the LDL receptor. (5) Internalizing of receptor– ligand complex into vesicles. (6) Sorting of the LDL receptor from the LDL particle via fusion with endosome. (7) Recycling of LDL receptors back to cell surface. (8) Lysosomal degradation of LDL particles into amino acids and cholesterol.
several metabolic biotransformations, including oxidation, scission, and degradation of the imidazole
ring, scission and degradation of the piperazine and dioxolane rings and oxidative O-dealkylation.Therefore,
the initial change in slope from 20 mg/kg may be explained by saturation of one or more of these metabolic
pathways.
The plateau in Cmax with the highest oral dose levels seems to be due to saturable, nonlinear, plasma protein
binding of KTZ enantiomers. Confirmation of saturation of this process was provided by the increases in unbound fraction of both enantiomers between 10 and 40 mg/L of racemate