Clinical Pharmacology Specialty Teaching Clinical Pharmacology Specialty Teaching

2006 2006 2007 2007

33. Pharmacokinetics, Pharmacodynamics and . Pharmacokinetics, Pharmacodynamics and
Pharmacogenetics Pharmacogenetics
Brian Tomlinson
Department of Medicine and Therapeutics,
The Chinese University of Hong Kong
Clinical Relevance of Pharmacokinetics S
Pharmacodynamics
ffect ffect
Plasma
concentration
Clinical outcome
Drug

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Pharmacokinetics
Concentration
in
blood
Cmax
Tmax
Elimination half life
Time
Basic pharmacokinetic parameters
AUC
ose response can be modified
by genetics or drug interactions
Concentration
in
blood
Oral
ose
Time
Ninimum effective concentration
!ncreased risk of toxicity
rug metabolism
Drug phase I phase II
metabolites metabolites
Oxidation Conjugation
Kidney
Gall
bladder
Urine
Bile
Cytochrome P4S0 (CYP) Superfamily
!soforms important in drug and
xenobiotic metabolism
CYP 1A1,2
CYP 2A6
CYP 2B6
CYP 2C8,3,18,13
CYP 2D6
CYP 2E1
CYP 3A3,4,S,7
Approximate fractions of drugs oxidized by
individual human P
4S0
enzymes
3A4
50%
2D6
30%
2C9/10
10%
1A2
4%
2A6
2%
2C19
2% 2E 1
2%
dapted from Michalets Pharmacotherapy 1998; 18:84112
testosterone
ethanol
warfarin
caffeine
propranolol
CYP3A4 is the major
isozyme constituting 60
of liver and 70 of gut
CYP4S0
Distribution of most common mutations in
CYP2D6 gene in Caucasians
Meyer UA & Zanger UM. Ann Rev PharmacoI ToxicoI 1997; 37: 269-96.
Chinese genotypes CYP2D6*10
nterethnic differences of
CYP2D6 allele frequencies
Ethnic
Group
NormaI
CYP2D6*1/2
%
Reduced
CYP2D6*10
%
Absent
CYP2D6*4
%
White 67 3 20
Asian 43 - 57 33 - 50 <1
Mayer U, Zauger UM, nn Rev Pharmacol Toxicol 1997; 37: 269
Propranolol disposition in Chinese
subjects of different CYP2D6 genotypes
mg single oral doses.
Genotype mean AUC
(nmol.hr/L)
C/C
188
333.9
C/T
188
58.7
T/T
188
766.1
dapted from ai M et al Clin Pharmacol Ther 1995; 58: 264-8
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(
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Time
Beta1adrenergic receptor haplotype
and BP response to metoprolol
0
2
4
6
8
10
12
14
16
18
SR/SR SR/CR SR/SC CR/SC
(n=12) (n=6) (n=1S) (n=7)
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Haplotypes:
SR, Ser43Arg383
SC, Ser43Cly383
CR, Cly43Arg383
P = 0.006
between groups
dapted from 1ohnson 1 et al Clin Pharmacol Ther 2003; 74: 44-52
rapefruit juice S felodipine

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Time
C
max
ater 5.5I3.
GFJ acute 17.9I3.3
GFJ 5 days 23.9I8.5
dapted from own KS et al 1 Clin Invest 1997; 99: 2545-53
dapted from Bailey DG et al Br 1 Clin Pharmacol 1998; 46: 101-10
100
100
30
CYP3A4
30
30
1S
CYP3A4
Crapefruit
juice
30
4S
CYP3A4
Small bowel
lumen
Liver sinusoid
Effects of
Crapefruit
juice on
felodipine
metabolism