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