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Psychobiology Research Group
Pharmacokinetics and Phamacogenetics
Hamish McAllister-Williams
PhD, MD, FRCPsych Reader in Clinical Psychopharmacology
Newcastle University
Hon. Consultant Psychiatrist Regional Affective Disorders Service
2
Declaration of Interests
• I have received: Speaker fees from:
• Astra Zeneca, BMS, Eli Lilly, GSK, Janssen-Cilag, Lundbeck, Organon, Pfiser, Wyeth
Consultancy fees from:• Astra Zeneca, BMS, Cyberonics, Eli Lilly, Janssen-
Cilag, Lundbeck, Servier, Wyeth
Independent investigator led research support from:
• Astra Zeneca, Eli Lilly and Wyeth
Pharmacokinetics
Barriers to drug delivery and effect
4
Dose
Conc in plasma
Conc in target organ
Effect
Absorption
Membrane transport
First pass metabolism
Volume of distribution
Half-life
Clearance
BBB or other
Membrane transport
Pharmacodynamics:
-EC50, slope
-Effect delay
-Tolerance
Pharmacokinetics and Pharmacodynamics
5
Pharmacokinetics
• Absorption
• Metabolism
• Elimination General principles Clinically relevant
examples
Theoretical plasma concentrations of three drugs with different rates of absorption
0
0.2
0.4
0.6
0.8
1
Time
Pla
sma
con
cen
trat
ion
(pro
po
rtio
n o
f d
ose
)
t
Peak concentration (Cmax)
max
Increased risk of toxicity
Minimum effective conc.
AUC
Absorption of TCAs• tmax
tertiary amines: 1 - 3 hours secondary amines: 4 - 8 hours
• Clinical relevance: shorter tmax leads to higher Cmax
most side effects (e.g. sedation, postural hypotension, membrane stabilisation) are dependent on the plasma concentration
therefore give sedative TCA all in one dose at night (and postural hypotension occurs while lying down!)
secondary amines often associated with fewer side effects
Quetiapine IR vs XL
9Datto et al. 2009 Clinical Therapeutics 31, 492
Quetiapine IR vs XL
10Datto et al. 2009 Clinical Therapeutics 31, 492
Quetiapine IR vs XL
11Datto et al. 2009 Clinical Therapeutics 31, 492
Quetiapine IR vs XL
12Datto et al. 2009 Clinical Therapeutics 31, 492
Sedation with quetiapine IR and XL
13Datto et al. 2009 Clinical Therapeutics 31, 492
Before treatment After 5 days treatment
Drugs
15
Fluoxetine
16
Drug Metabolism
17
O
Type 1 metabolismCytochrome P450’sOxidation etc
Type 2 metabolismConjugationGluconurilation etc
Conjugation
Polar species
Elimination Biliary elimination
Non-polar species
Metabolism of TCAs - 1• Type 1 metabolism converts tertiary to secondary amines,
eg. Amitriptyline Nortiptyline Imipramine Desipramine Clomipramine Desmethylclomipramine
• Tertiary amines generally more potent 5-HT uptake blockers, secondary amines more potent NA uptake blockers Up to 70% of clomipramine may be converted to
desmethylclomipramine • may lead to lack of efficacy in OCD
Metabolism of fluoxetine
19
Morphine Morphine glucuronate
Cytochrome P450 2D6
20
http://medicine.iupui.edu/clinpharm/ddis
21
22
23
CYP 450 – 1A2 interaction examples
• Substrates: Tertiary amine TCAs Clozapine
• Inhibitors Fluvoxamine, Ciprafloxacin
• Inducers Brocolli, Brussel sprouts, tobacco, modafanil
24
CYP 450 – 2D6 interaction examples
• Substrates TCAs, paroxetine, haloperidol, risperidone
• Inhibitors Fluoxetine, paroxetine Duloxetine Cimetidine, sertraline
• Inducers Dexamethasone
25
CYP 450 – 3A4,5,7 interaction examples
• Substrates Many and varied drugs Dexamethasone, tamoxifen
• Inducers St John’s wort Glucocorticoids
26
Elimination of drugs
• Primarily via the kidney Metabolism of drug usually has to occur first to
produce a water soluble compound This is usually the rate limiting step Factors slowing metabolism will increase the
elimination time
• Kinetics Usually ‘first order’ Influences the dosing schedule Influences the possibility of withdrawal problems
0 1 2 3 4 5 6 7 8 9 10
Time (hours)
0
50
100
150
200
Pla
sma
alco
hol c
once
ntra
tion
(mg/
dl)
Zero order kinetics
• The rate of elimination is independent of plasma concentration
• A small change in dose can produce a big change in plasma concentration
• Rare except if elimination process is saturated (can occur with TCAs)
0 10 20 30 40 50 60 700
10
20
30
40
Time (hours)
Pla
sma
war
fari
n co
ncen
trat
ion
(ug/
ml)
First order kinetics
• The rate of elimination is proportional to the plasma concentration
• Elimination rate quantified by ‘half life’
• The majority of drugs have first order kinetics
tt1/21/2 tt1/21/2
Theoretical plasma concentration of a first order drug after single or repeated doses
0
1
2
0 1 2 3 4 5 6
Time (number of half-lives)
Pla
sma
Dru
g C
once
ntr
atio
n
(pro
por
tion
of
dos
e)
Doses
Effect of reduced metabolism of a drug on its steady state concentration
240 4 8 12 16 20
Time (hours)
Pla
sma
dru
g co
nce
ntr
atio
n
t = 4 hours
(due to reduced
clearance)
1/2
t = 2 hours1/2
Half lives of TCAs
Amitriptyline
Imipramine
Clomipramine
Nortriptyline
Desipramine
DMC
Lofepramine
Half Life
(hours - approx)
16
12
18
60
50
45
5
Metabolite
Nortriptyline
Desipramine
DMC
Desipramine
“…prescribing phenothiazines and tricyclic antidepressants three times a day is simply a public display of pharmacological ignorance…”
R.E. Kendell (1993)
Companion to Psychiatric Studies, 5th Ed. p 419
Effect of varying dose and frequency of administration of a first order drug
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
0 1 2 3 4 5 6Time (number of half-lives)
Pla
sma
dru
g co
nce
ntr
atio
n
Half dose,
same freq.
Control
Half dose,
twice as often
Increased risk of side effects
Half lives of SSRIs - 1
• Note inter-drug and -individual variation
• Fluoxetine and paroxetine t1/2 increases with dose
and time
Fluoxetine
Sertraline
Citalopram
Paroxetine
Fluvoxamine
Half life (hrs)
(Active metab.)
45-72 (150-200)
25 (66)
36 (?)
10-20
15
Half lives of SSRIs - 2Clinical Relevance
• Fluoxetine/norfluoxetine long half life consequences: 5+ weeks to steady state late emergence of plasma level dependent side effects prolonged washout period
• N.B. delayed CYP2D6 inhibition benefit for poor compliers little risk of discontinuation syndrome
• Paroxetine short half life SSRI most prone to discontinuation
• N.B. also anti-cholinergic
Pharmacokinetics Conclusions
• A knowledge of pharmacokinetics can improve the clinical usage of drugs e.g. by: minimising side effects associated with Cmax
• split dosages• choice of drug (secondary versus tertiary TCA, IR vs XR)
adjusting dosages appropriately for age and sex avoiding pharmacokinetic interactions being aware of discontinuation phenomena