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Chapter 3
Pharmacokinetics
Distribution
Drug
Metabolism
or Excretion
Elimination
Drug Concentration
at Site of Action
Pharmacologic Effect
Clinical Response
Toxicity
Efficacy
Pharmacodynamics
Drug
Concentration in
Systemic
Circulation
Pharmacokinetics
Drug in
Tissues of
Distribution
concentration-effect
Absorption
dose-concentration
Drug Administration
2
 Drug Transport
 Process of Drug in vivo
 Elimination Kinetics
3
Section 1
Drug Transport
Chapter 3
4
Modes of Transport
1. Filtration
Passive transport
2. Simple diffusion
3. Carrier-mediated transport
1) Facilitated diffusion
2) Active transport
5
1. Filtration
 Aqueous diffusion, Aqueous channel;
 Hydrosoluble , driven by concentration gradient
6
1. Filtration
 Downhill movement.
Flux (molecules per unit time) =
Area  Permeabili ty coefficient
C1  C2 
Thickness
7
Simple diffusion
 Lipid diffusion
 The most common transport for drug
8
2. Simple Diffusion, Passive Diffusion
 Ion trapping :
– Nonionized form (uncharged) : low polarity,
hydrophobe, lipid soluble, permeation through
membrane
– Ionized (charged) : high polarity, hydrophil,
lipid unsoluble, unable permeation through
membrane
9
Ionization of weak acid and weak
bases
 A weak acid is best defined as a neutral molecule that
can reversibly dissociate into an anion and a proton.
C8H7O2COOH
Neutral
aspirin
C8H7O2COO- +H+
Aspirin anion
proton
10
Ionization of weak acid and weak
bases
 A drug that is a weak base can be defined as a neutral
molecule that can form cation by combining with a
proton.
C12H11CIN3NH3 +
Pyrimethamine
cation
C12H11CIN3NH2+H+
Neutral
pyrimethamine
Proton
11
pH & pKa determine the degree of dissociation of drug
 pH and pKa are important in determining the fraction in the
un-ionized form.
 pKa : the pH at which 50% of the molecules in solution are in
the ionized form.
12
pH & pKa determine the degree of dissociation of drug
Weak acid
Weak base
HA  H   A
B  H   BH 
[ H  ][ A ]
Ka 
[ HA]
[ H  ][ B]
Ka 

[
BH
]
dissociation constant
[ A ]
[ B]
pKa  pH  log
pKa  pH  log
[ HA]
[ BH  ]
[ A ]
pH  pKa  log
[ HA]
10 pH  pKa
[ A ]

[ HA]
[ B]
pH  pKa  log
[ BH  ]
[ B]
pH  pKa
10

[ BH  ]
13
 Henderson-Hasselbalch equation:
(Protonated )
log
 pK a  pH
(Unprotonated )
 The lower the pH relative to the pKa, the greater will be
the fraction of drug in the protonated form.
 The protonated form of a weak acid is the neutral, more
lipid-soluble form.
 The unprotonated form of a weak base is the neutral form.
14
Application of HendersonHasselbalch Equation
 Lipid-soluble form is reabsorbed by renal tubule
 Weak acids are excreted faster in
alkaline urine;
weak bases are excreted faster in acidic urine
 Acidification: NH4Cl, Vc
 Alkalinization: NaHCO3, Acetazolamide(乙酰唑
胺）
16
Quiz

We orally administer a weak acid drug(A) with a pKa of 3.4.
Gut pH is 1.4, and blood pH is 7.4. Assume the drug crosses
membranes by simple passive diffusion. Which of the
following observations would be true?
A.
Only the ionized form of drug, will be absorbed from the gut.
The drug will be hydrolyzed by reaction with HCl and so cannot be
absorbed
The drug will not be absorbed unless we raise gastric pH to equal pKa,
as might be done with an antacid
The drug would be absorbed, and at equilibrium the plasma
concentration of the A- would be 10000 times than the plasma
concentration of nonionized moiety(HA)
B.
C.
D.
17
3. Carrier-Mediated Transport
Carrier-mediated
 Active
transport
 Facilitated transport
18
3. Carrier-Mediated Transport
Trans-membrane protein
– Selectivity/specificity
– Saturation
– Competitive inhibition
 Active transport
– Against gradient
– Energy required
 Facilitated transport
– Down gradient
– Energy free
19
Chapter 2
Section 2
Process of Drug in vivo：
Absorption, Distribution, Metabolism, Excretion
20
Ⅰ、Absorption
Process of drug leaving site of administration into systemic
circulation.
 Inhalation
 Intranasal
 Intravenous







Infusions, Intravenous
Injections, Intravenous
Mucosal
Ophthalmic
Oral
Buccal
Sublingual
Rectal
Topical
21
Buccal/Sublingual
 absorbed though oral mucus membranes in
mouth
– buccal = cheek
– sublingual (SL) = under tongue
22
First pass elimination (first pass
metabolism, first pass effect )
 pass through liver
before reaching
circulation
 undergo metabolism by
liver
Bioavailability


Bioavailability refers to the extent and rate at
which the drug enters systemic circulation,
thereby accessing the site of action.
If the drug is given by extravascular
administration, less than 100% of a dose reach
the systemic circulation.
24
Bioavailability (F)
AUC (area under the curve): The area under the plasma drug concentration-time
curve , reflects the actual body exposure to drug after administration of a dose of the drug
and is expressed in mg*h/L . It is directly proportional to the total amount of drug in the
patient's blood.
A
F=
 100%
i.V
D
F=
AUC P.O
p.o
AUC I.V
25
Routes of Administration, Bioavailability, and
General Characteristics.
Route
Bioavailability(%)
Characteristics
Intravenous (IV)
100 (by definition)
Intramuscular (IM)
75 to ≤ 100
Large volumes often feasible; may be painful
Subcutaneous (SC)
75 to ≤ 100
Smaller volumes than IM; may be painful
Oral (PO)
5 to < 100
Most convenient; first-pass effect may be
significant
Rectal (PR)
30 to < 100
Less first-pass effect than oral
Inhalation
5 to < 100
Often very rapid onset
Transdermal
80 to ≤ 100
Usually very slow absorption; used for lack of
first-pass effect; prolonged duration of action
Most rapid onset
Ⅱ、Distribution


Drug goes to organs and tissue from circulation via its
permeation
Dependent on its solubility, the rate of blood flow to
the tissues, and the binding of drug molecules to
plasma proteins
27
1. Plasma protein binding
 Free drug
Bound drug
D  P  DP
D is free drug ，DP is bound drug
[ D][ P]
 KD
[ DP ]
If PT is total amount of plasma protein, then
[ DP ]
[ D]

[ PT ] K D  [ D]
28
 Unbound drug = active
 Reversible equilibrium
 Saturable: albumin, most common protein to bind
drugs
 Nonspecific & competitive
Drug and Drug (especially, drug of high binding
rate): phenylbutazone + warfarin
Drug and Endogenetic substance: billirubin
29
plasma
protein
A drug: 99%
Free A drug: 1%
+
B drug：98%
Free A drug: 2%
Effect increase,
even toxicity
30
Distribution
Body’s barriers :
 Blood-brain barrier (BBB) :
1.
2.
Tight junction between endothelial cells
Astrocyte surrounding the endothelial cells
 Placental-barrier
 Blood-eye-barrier
31
血脑屏障
(Blood-brain
barrier, BBB)
由毛细血管
壁和N胶质细
胞构成
Ⅲ、 Metabolism, Biotransformation

Sites of biotransformation
– liver
– Others: GIT, kidneys, brain, & plasma
33
Results of metabolism :
1.transform into inactive substance;
2.inactive drug (pro-drug) → active metabolite;
Codein
morphine
3.active drug → other active substance;



Phenylbutazone(保泰松) and oxyphenbutazone（羟基保泰松）
Diazepam (安定) and oxazepam（去甲羟基安定）
Carbamazepine (卡马西平) and 10, 11-epoxide carbamazepine
（环氧卡马西平）
4. transformed into toxicant.

Isoniazid → acetyl isoniazid
34
Steps of Metabolism
 Phase Ⅰ
– oxidation, reduction and hydrolysis
 Phase Ⅱ
– Conjugation with endogenous
compounds(glucuronic acid , glycine, sulfuric acid)
35
matabolism
Phase I
inactivaed
Phase II
bound
Drug
Excretion
activityor
Drug
bound
bound
Drug
Lipophilic
Hydrophilic
36
Metabolism Enzyme
 Specific enzymes
– cholinesterase, monoamine oxidase (MAO), etc.
 Non-specific enzymes
– hepatocyte microsomal enzymes (cytochrome P450
enzyme system, CYP 450).
– These isozymes involved in Phase I reactions.
– If binds to carbon monoxide , spectrum with a maximum at
450 nm
37
CYP1A1/2
Non-CYP
enzymes
CYP1B1
CYP2A6
CYP2B6
CYP2C8
CYP2C9
CYP2C19
CYP3A4/5/7
CYP 2D6
CYP2E1
38
Characteristic of hepatic drug enzyme
 low selectivity
 great variability
 enzyme activity is liable to be influenced by
outside factors.
– enzyme inducer
– enzyme inhibitor
39

General inducers:
苯妥英phenytoin、奎尼丁quinidine 、利福平rifampicin、
卡马西平carbamazepine、灰黄霉素griseofulvin、巴比妥
类 barbiturates（苯巴比妥为最） 、 甲丙氨酯
meprobamate，格鲁米特glutethimide、保泰松
butazodine 、 chronic alcoholic intoxication 慢性酒精中
毒

General inbibitors:
酮康唑 Ketoconazole 、西咪替丁cimetidine、异烟肼
isoniazide、红霉素erythrocin、磺胺sulfonamide、氯霉
素chloramphenicol，柚子汁 grapefruit juice，acute
alcoholic intoxication 乙醇急性中毒者
40
利福平
环孢素
伊曲康唑
麦芽汁
Ⅳ、 Excretion
 Drug or metabolite → emunctory(排泄器官) or
secretory(分泌器官)→ outside of body
 Excetion organ:
– kidney
– bile duct
– intestinal tract
– salivary gland(唾液腺)
– galactophore(乳腺)
– sudoriferous gland(汗腺)
– lung
42
Excretion
 Renal excretion: glomerular
filtration, active tubule
secretion, passive tubule
reabsorption.
43
2. 胃肠道：胆汁-粪便途径
胆汁排泄
(biliary excretion)
Liver
和
肝肠循环
Bile duct
(Enterohepatic
recycling)
Gut
Portal vein
Feces
excretion
Chapter 2
Elimination Kinetics
45
Kinetic process
 Drug elimination kinetics is the eliminating course of plasma
or blood concentration of drug with its distribution,
metabolism and excretion. It is expressed by mathematics
equation:
dc
  KC N ( N  0)
dt
This rate process is called N grade rate process. where K is
rate constant, Minus of right-sideness denotes reduction of
drug concentration.
46
k：Rate constant for
elimination
Rate of elimination is proportional to C.
t ½ is a constant
Zero order elimination kinetics
n=0
dC/dt = -k
Rate of elimination is independent to C.
t ½ is variable
Log Units of Drug
Firstorder elimination kinetics
n=1
dC/dt = - kC
Units of Drug
dC/dt = - kCn
n=1
n=0
n=0
n=1
Time
T1/2: The time it takes for the [drug] in the body to be reduced by 50%
Comparison
Zero-order Kinetics
First-order Kinetics
Contant Rate Process
Rate is proportional to the drug
concentration
dC/dt = -K0
dC/dt = - KC
t1/2 =0.5C0/K0 , depends on initial
drug concentration
t1/2 =0.693/K , independent and is
a constant value
Most drugs
Ethanol, phenytoin, aspirin
Capacity-limited elimination,
carrier based processes after
saturation
Not linked with carriers or
unsarurable if linked with carriers
48
Section 4
Compartment Model
房室模型
One compartment model
一室模型
 Considers the body to
be a single
compartment. A drug is
absorbed , immediately
distributed, and
subsequently
eliminated by
metabolism and
excretion.
D
Ka
D
Ke
D
Two compartment model
二室模型
 Central compartment：plasma, heart, lung, kidney,
endocrine system, et al
 Peripheral compartment： muscle, fat tissue, bone,
et al
 Most drugs are transported with two compartment
model
Central
compartment
D
Ka
K12
D
D
Distribution
Ke或
K10
K21
Peripheral
compartment
D
Two compartment model
Ct = Ae
-a×t
+ Be
- b ×t
52
Chapter 2
Section 5
Important Parameters in
Pharmacokinetics
53
1. Volume of distribution,Vd
Vd: theoretical volume that the total amount of
administered drug would have to occupy (if it were
uniformly distributed), to provide the same concentration as
it currently is in blood plasma.
Vd relates the amount of drug in the body to [C] of drug in
blood or plasma
Vd＝D／C0
D for total dose of drug
C for concentration in plasma
―C0 equilibrium of distribution
54
significances：

Understand the drug distribution in the
body：
70kg person
•
•
•
•

Vd≈5L indicates in the plasma，
42L Body fluid
Vd≈30-40L in the total body fluid，
Vd＞40L in the tissue and organs，
Vd ＞100L in the specific organ or big range tissues，
e.g thyroid , Skeleton, adipose tissue
Needed to calculate a loading dose ：
D=Vd×C
55
2. Clearance, CL
― Definition: volume of blood which is cleared off a
drug per unit of time
Rate of eliminatio n (RE)
CL 
(ml/min or L/h)
C
RE kidney
CLkidney 
C
RE liver
CLliver 
C
RE other
CLother 
C
CLsystem  CLkidney  CLliver  CLother
56
Calculations：
1. Cl is constant in first-order kinetics
CL ＝KeVd
Reasoning:
RE  K e A
Cl  Ke  A / C
Cl  RE / C
Vd  A / C
Cl  Ke Vd
Calculations：
2. CL ＝A / AUC （A for total drug in body, = dose）
Reasoning:

RE  K e A
A
Vd 
 A  Vd C
C
RE K e A K eVd C
 CL 


 K eVd
C
C
C
C
C
 AUC 
 Ke 
Ke
AUC
CVd
A
 CL  K eVd 

AUC AUC
Half-life, T1/2
Definition: The time it takes for the [drug] in the body to be reduced by 50%
First-order
Elimination Kinetics
(linear kinetics)
 Cl  Ke Vd
as
 t1/ 2
Vd
 0.693
Cl
Constant repeated administration of drugs
Steady-state concentration
Aim to let MTC>Css>MEC
Css-max < MTC
Css-min > MEC
Additive amount of eliminated drug
T1/2
sum
1
2
3
4
5
50
25
12.5
6.25
3.125
50
25
12.5
6.25
50
25
50
12.5
25
93.5
50
96.5
50
75
87.5
61
Drug
Concentration(ug/ml)
MTC
MTC
MEC
MEC
时间(半衰期)
时间(半衰期)
Css is proportional to dose
and dosing interval
62
Css = AUCss/ τ
63
Chapter 2
Section 6
Dosage design and Optimization
64
1. target concentration
Steady-state concentrion（Css）
Css-max < MTC
Css-min > MEC
65
Maintenance dose (MD)
To maintain SS , the dosing rate must equal to
the rate of elimination. That is
dosing rate = rate of elimination

TC : Target concentration
MD= CL×TC×Dosing interval
66
Loading Dose
 Loading dose is dose required to achieve a specific
plasma drug concentration level immediately with a
single administration.
67
首剂加倍
F  DL  F  DL e
DL 
Dm
DL 
Dm
 Ke 
 F  Dm
 Ke 
1 e
当  t1/ 2时，
1 e
 Ke 

Dm
1 e

ln 2
t1 / 2
t1 / 2
Dm

 2 Dm
1
1
2
即每隔一个t1/2给药一次时，负荷量为
维持量的2倍。
The target concentration strategy
1. Choose the target concentration, TC.
2. Predict volume of distribution (Vd) and clearance (CL) based
on standard population values with adjustments for factors
such as weight and renal function.
3. Give a loading dose or maintenance dose calculated from TC,
Vd, and CL.
4. Measure the patient's response and drug concentration.
5. Revise Vd and/or CL based on the measured concentration.
6. Repeat steps 3–5, adjusting the predicted dose to achieve TC.

69
Important Pharmacokinetics Calculations
 Single-Dose Equations
– Volume of distribution (Vd):
– Half-life (t1/2):
Vd 
D
C0
t1/ 2  0.7 
 Multiple Doses or Infusion
Rate Equations
– Loading dose (LD):
– Maintenance dose (MD):
Vd
CL
k0  CL  Css
LD 
Vd  C p
MD 
F
CL  Css 
F
 Brian is a 15 yr old patient who has been
admitted to the hospital with a severe case of
bacterial septicemia caused by a gram-negative
organism that has been determined to be
sensitive to Gentamycin. Gentamycin’s Vd=20
L. What i.v. loading dose would you give Brian
to rapidly achieve a therapeutic plasma level of
5 mg/L?
A. 20 mg B. 25 mg C. 50 mg D. 100 mg E. 250 mg
D
 The following graph shows the elimination time
course obtained after giving a 320 mg dose of a
drug by both i.v. & oral routes. From the data
shown, calculate the drugs elimination clearance.
You may need to use a calculator.
A. 0.6 L/hr
B. 1.75 L/hr
C. 10 L/hr
D. 32 L/hr
E. 36 L/hr
72
AIM get Cl,
Vd
Cl  0.693
t1/ 2

1st to Calculate Vd,

Vd ＝D／C0

Vd ＝320mg/32ug/ml=10L

2nd to get t1/2

t1/2=4h

Cl=0.693×10L/4h=1.75L/h
This formula can be used to calculate both Vd,
t1/2 & Cl after giving a single drug dose
Original question from USMLE
Your pediatric patient is suffering from a bacterial
infection & requires maintenance dosing with
gentamicin. Gentamicin’s elimination clearance
is 5.0 L/hr. What maintenance i.v. dose of
gentamicin should you give every 8 hours to
maintain an average steady-state plasma level
of 5 ug/ml?
D
A. 25 mg B. 50 mg C. 100 mg D. 200 mg
74
The end