Basics of Pharmaco-/ Toxicokinetics - ddnz.uzh.ch
60
Basics of Pharmaco-/ Toxicokinetics Dr. Robert Doblhofer www.granzer.biz
Transcript of Basics of Pharmaco-/ Toxicokinetics - ddnz.uzh.ch
Basics of Pharmaco-/ Toxicokinetics
Dr. Robert Doblhoferwww.granzer.biz
Agenda
Introduction
A Absorption (esp. after oral ingestion)
D Distribution
M Metabolism
E Excretion
Concentration in plasma and derived pharmaco-/toxicokinetic parameters
(Possibilities and limitations of pharmaco-/toxicokinetics)
2
Material
Pharmakokinetik: Derendorf, Gramatté, Schäfer
Parameter zur modellunabhängigen PK: Cawello
Arzneimittelwirkungen: Mutschler
Funktionelle Histologie der Haussäugetiere, Liebich
Der Körper des Menschen: Benner
3
4
INTRODUCTION
5
Friedrich Hartmut Dost (Pediatrician), 1953 6
7
8
ABSORPTION
ca. 0,1 m2 > 100 m2
Gastro-Intestinal Tract
9
10
Gain of Surface in the Intestines
10
11
Gain of Surface in the Intestines
11
12
)( ia CCLFDq −⋅⋅=
q = rate of diffusion
D = diffusion-constant
F = membrane surface
L = membrane thickness
Ca = concentration in intestinal lumen
Ci = concentration in intestinal epithelial cell
Fick`s Law (Passive Diffusion)
12
cell membrane
Ca Ci
passive diffusionuncharged, amphiphilic, driven byconcentration gradient Ca > Ci
diffusion through poressmall, hydrophilic
active transportglucose, amino acids, Na+,…
carrier-mediated diffusion
pinocytosis
efflux transporter
phagocytosis
Absorption Processes at the Intestinal Wall
13
solubilitydissolution rate particle size
Substance is dissolved
Substance is uncharged
Substance is amphiphilic
- H+
pka
amphiphilic
intestinal epithelial cell
Bloo
d ca
pilla
ry
Requirements for Passive Diffusion
14
Blood Flow in Villi
15
16
DISTRIBUTION
Total body water (~60%) Blood (~8%)
Plasma proteins Blood cells (esp. erythrocytes) Fatty tissue (highly lipophilic substances, e.g. DDT) Bones (Ca2+-mimetics, e.g. Pb2+, Sr2+)
Distribution Spaces
total body water~42 l (0.6 l/kg)
interstitial water~15 l (0.2 l/kg)
plasma water~3 l (0.04 l/kg)
intracellular water~24 l (0.35 l/kg)
extracellular water~18 l (0.25 l/kg)
17
Examples: blood-brain-barrier kidney, intestines liver
Blood-to-Tissue Transit from Capillaries
A: closed capillary B: fenestrated capillary C: open capillary with discontinuous endothelium
18
19
METABOLISM
Metabolism
Phase I: Activation Mainly CYP450 enzymes Localization of CYPs: Liver Intestines Lung Kidney Skin Blood…
Phase II: Conjugation Glucuronidation Sulphatation Acetylation Conjugation with GSH …
improved aqueous solubility glomerular filtration
20
First-Pass-Effect
CAVE: no/limited FPE after sublingual and rectal administration!21
22
EXCRETION
Biliary Excretion
23
The Kidney
24
The Nephron
25
cut-off: ~70.000 Da (see below)
Glomerular Filtration
26
Glomerular Filtration
27
Glomerular Filtration
28
Pharmacokinetics = ADME
Absorption: uptake into the (blood-)circulation
Distribution: via blood, different types of capillaries
Metabolism: phase I: activationphase II: conjugation (solubility ↑)first-pass-effect after oral administration
Excretion: via urine (glomerular filtration in the kidney)and bile (liver)
Summary Part I
29
30
CONCENTRATION IN PLASMA AND DERIVEDPHARMACO-/TOXICOKINETIC PARAMETERS
tkCtC ⋅−= 00)(
Time0 2 4 6 8 10
Con
cent
ratio
n in
Pla
sma
0
20
40
60
80
100
120
0kdtdC
=−
Zero-Order Kinetics („Saturation“)
31
CkdtdC
⋅=−
eCtC tk ⋅−⋅= 0)(
Time0 2 4 6 8 10
Con
cent
ratio
n in
Pla
sma
0
20
40
60
80
100
120
tkCC ⋅−= 0lnln
tkCC ⋅−=303,2
loglog 0
Time0 2 4 6 8 10
Con
cent
ratio
n in
Pla
sma
0,01
0,1
1
10
100
1000
First-Order Kinetics („Linear PK“)
32
Time0 2 4 6 8 10
Con
cent
ratio
n in
Pla
sma
0
20
40
60
80
100
120
eCtC tk ⋅−⋅= 0)(
tkCC ⋅−= 0lnln
Conc. halved
2/100 ln
2ln tkCC
⋅−=
2/100 ln2lnln tkCC ⋅−=−
kt 2ln
2/1 =
kt 693,0
2/1 =
2/0CC = 2/1tat
The Half-life in First-Order Pharmacokinetics
33
Time0 2 4 6 8 10
Con
cent
ratio
n in
Pla
sma
0,01
0,1
1
10
100
1000
t1/2 = 0,693/kSlope = -k/2,303 (ln/log)
Unit of half-life:t1/2: hk: 1/h resp. h-1
The Half-life in First-Order Pharmacokinetics
34
Vmax = maximum rate of metabolism/elimination
KM = Michaelis-Menten-constant (=C at Vmax/2)
Vd = volume of distribution (for in vivo studies)
dM VCKCV
dtdC
⋅+⋅
=−)(
max
Michaelis-Menten-Kinetics
Non-Linear Pharmacokinetics
35
dM VCKCV
dtdC
⋅+⋅
=−)(
max
C>>KM → (KM+C) ≈ C
dVV
dtdC max
=−
Case 1:high concentration/dose:zero-order kineticssaturation (non-linear)
C<<KM → (KM+C) ≈ KM
CVK
VdtdC
dM⋅
⋅=−
max
Case 2:low concentration/dose:first-order kineticslinear pharmacokinetics!
Michaelis-Menten-Kinetics
36
Michaelis-Menten-Kinetics
37
Time0 2 4 6 8 10
Con
cent
ratio
n in
Pla
sma
0
20
40
60
80
100
120
AUC [µg·h/ml]
The Area under the Curve (AUC)
38
eCtC tk ⋅−⋅= 0)( ∫ ⋅=−
z
z
t
t dttCAUC0
0 )(
)1(00
zz
tkt e
kCAUC ⋅−
− −⋅=
kCAUC 0
0 =∞−
The Area under the Curve (AUC)
39
Time0 2 4 6 8 10
Con
cent
ratio
n in
Pla
sma
0
20
40
60
80
100
120
AUC: The Linear Trapezoidal Rule
40
Time0 2 4 6 8 10
Con
cent
ratio
n in
Pla
sma
0
20
40
60
80
100
120
tz
Cz
AUC0-tz vs. AUC0-∞
41
Time0 2 4 6 8 10
Con
cent
ratio
n in
Pla
sma
0,1
1
10
100
1000
tz
Cz
AUC0-tz
AUC0-tz vs. AUC0-∞
kCAUC z
tz =∞− (max. ~20%)
42
The Volume of Distribution
CXVd =
0CDoseVd =
X = amount of compound present in the body
The amount of compound present in the body (X)is best known immediately after an iv dose.
VXC =
dP V
XC =
X X
CTissue > CPlasma
A: „no distribution“ B: distribution to tissue
43
The Volume of Distribution - Example
3 gC = 1 g/l
0.03 gC = 0.01 g/l
2.97 g
3 g 3 g
Vd = 3 Liter Distribution only
to plasma
44
3 l plasma
Vd = 300 Liter Distribution
to tissue
plasma
fatty tissue
Time0 2 4 6 8 10
Con
cent
ratio
n in
Pla
sma
0,01
0,1
1
10
100
1000
-k/2,303
C0
Vc = Dose/C0
Unit:Vc: l (Liter)
The Volume of Distribution
45
The Volume of Distribution
Reference volumes in the body (70 kg):
total body water~42 l (0.6 l/kg)
interstitial water~15 l (0.2 l/kg)
plasma water~3 l (0.04 l/kg)
intracellular water~24 l (0.35 l/kg)
extracellular water~18 l (0.25 l/kg)
46
rate of elimination: XkdtdE
e ⋅=
AUCDose
CDosekVk
CXk
CCL ede
edtdE
=⋅=⋅=⋅
==0
volume of distribution:0C
DoseCXVd ==
AUC:ek
CAUC 0=
D
X Eke
i.v.
The Clearance
47
AUCDoseVkCL de == [l/h] or [l/h·kg]
Compare:liver blood flow: ~1,5 l/minrenal plasma flow: ~0,6 l/min
hhh QCL ε⋅=
The Clearance
48
Clearance:proportional to: Vd
antiproportional to: AUC; t1/2
D
X Eke
i.v.
Compartments
Time0 2 4 6 8 10
Conc
entra
tion
in P
lasm
a
0,01
0,1
1
10
100
1000
49
D
X Ukr
i.v.
M
km
ke = kr + km
Compartments
Time0 2 4 6 8 10
Conc
entra
tion
in P
lasm
a
0,01
0,1
1
10
100
1000
50
D
Xc Eke
i.v.
Xp
ADosisVz =
Compartments
51
D
X Eke
p.o.
Aka
XkAkdtdX
ea ⋅−⋅=
)()(
tktk
ead
ap
ae eekkV
DFkC ⋅−⋅− −⋅−⋅⋅⋅
=
Bateman-Function
Oral Administration
52
Oral Administration: Bateman-Function
53
Oral Administration: Bateman-Function
Cmax
tmax
54
AUC always identical! Extreme: immediate absorption = iv-curve
CLDFAUC ⋅
= → %)100((%) ⋅=iv
po
AUCAUCF
Oral Administration: Bateman-Function
55
Multiple-Dose PK: „Cumulation“
ss = steady state; sd = single dose; τ = dosing interval
τ(sd)
τ(ss)
AUCAUC
R−
−=0
0„Cumulation“: 2121
1
/tτR
−
−
=
56
Multiple-Dose PK: „Accmulation“
τAUC
C τ(ss)P,ave(ss)
−= 0
„Accumulation“:
10
0 =∞−
−
(sd)
τ(ss)
AUCAUC
10
0 >∞−
−
(sd)
τ(ss)
AUCAUC
(toxicologically relevant!)
57
Linear PK only when saturation does not occur
Very high doses can lead to non-linear PK
First order PK: exponential decrease of CP
t1/2, AUC, Vd und CL
Oral administration: Bateman-Funktion (ka/ke), Cmax, tmax, AUC
Bioavailability F = AUCpo/AUCiv
A high bioavailability does not necessarily lead to high plasmaconcentrations (if the clearance is high)
(Ac-)cumulation is not necessarily of toxicological relevance
Summary Part II
58
Summary Part II
Parameter Meaning iv po
VC / VZ central/apparent volume of distribution X
CL total body clearance X
t1/2 half-life X (X)
AUC0-∞ infinite AUC (extrapolated to infinity) X (X)
AUC0-t observed AUC X X
Cmax highest observed concentration in plasma X
tmax time, at which Cmax is reached X
F (oral) bioavailability X
59
60
Dr. Robert DoblhoferGranzer Regulatory Consulting & Services GmbH
Kistlerhofstraße 172C
81379 München
Tel: +49 (0)89 780 68 98 - 53
THANK YOU!
