Transcript 酸枣仁油软胶囊的新药开发研究

PHARMACOLOGIC PRINCIPLES
CHAPTER 3
Pharmacokinetics
（ body acts on drug ）
Undergoing of drugs in body
(sites of action)
binding
free
pharmacokinetics
(accumulation)
free
binding
distribution
drugs
(plasma)
(renal)
absorption
distribution
Free drugs
excretion
po sc im
peroral
subcutaneous
intramuscular
binding drugs metabolites
distribution
transport
transformation
Metabolism
(liver)
out of body
permeation across membranes
pharmacokinetics
Ⅰ.Drug permeation across membranes
1. membrane
The membranes with pore are composed of lipids and
proteins in a ratio of 70:1. The liquid-form double-deck of
membranes is formed from lipid molecules; The special
proteins inserted into the double-deck are receptors,
enzymes, ion channels, carriers……
Facilitated
lipid
diffusion filtration transport
Active
transport
High concentration
ectoATP
membrane
Intrapore
fenestrated membrane
carrier
Low oncentration
permeation across membranes
pharmacokinetics
2. Passive transport across membranes
(down hill)
A drug molecule moves from
a side of membrane relatively
high concentration to another
side of low concentration
without requiring energy, until
an equilibrium has been
achieved on both sides of the
membrane.
high
…..
…..
…..
…..
…..
low
..
…..
…..
…..
…..
…..
…..
…..
…..
…..
..
…..
…..
…..
…..
equilibrium
Lipid diffusion; Filtration; Facilitated transport
permeation across membranes
pharmacokinetics
1) Lipid diffusion ( Simple diffusion)
The most important mechanism of drug transport
Drug movement across membranes is driven
by a concentration gradient after solution in the
lipids of membranes.
pH (pKa) ┐
Nonionized form
more lipid soluble
easy permeation
less polar molecules
pKa is pH when Ionized rate is 50%
k1
k2
Ionized form
less lipid soluble
hard permeation
polar molecules
ion trapping
Lipid diffusion
HA (weak acids)
HA
k1
k2
H+＋A-
k1
[H+][A-]
Ka＝──＝─────
k2
[HA]
[A]
pKa＝pH－log ───
[HA]
[A-]
pH－pKa＝log ───
[HA]
[A-]
───＝10pH－pKa
[HA]
pharmacokinetics
B (weak bases)
B＋H+
k1
BH+
k2
k1
[H+][B]
Ka＝──＝ ────
k2
[BH+]
[B]
pKa＝pH－log ───
[BH+]
[B]
pH－pKa＝log ───
[BH+]
[B]
───＝10pH－pKa
[BH+]
Lipid diffusion
[A-]
───＝10pH-pKa
[HA]
weak acids
★ pH↑↓→[A-]↑↓
→ionization↑↓
→lipid solution↓↑
→permeation↓↑
pharmacokinetics
[B]
───＝10pH-pKa
[BH+]
weak bases
★ pH↑↓→[BH+]↓↑
→ionization↓↑
→lipid solution↑↓
→permeation↑↓
Conclusion:
Neither weak acids or weak bases are dissolved in same acid-base
solution, the lipid solution↑, permeation↑;
They are dissolved in opposite acid-base solution, the lipid
solution↓, permeation↓.
More polar (molecules), less permeation; Less polar, More
permeation
Lipid diffusion
pharmacokinetics
For example, Bicarbonate (NaHCO3)
is very effective for treatment of acute
toxication from weak acid drugs (like
barbiturates).
why？
Lipid diffusion
pharmacokinetics
① Alkalization of gastric juice →ionization↑
→ permeation↓ →absorption ↓
pH
↑
>
pH
blood
gastric juice
[A-]↑ > [A-]
drug
drug
Gastrolavage of NaHCO3
② Alkalization of blood plasma →
permeation↓→across blood-brain barrier↓
pH↑> pH
Cerebrospinal
blood
[A-]↑> [A-]
fluid
drug
drug
Intravenous drop of NaHCO3
Lipid diffusion
pharmacokinetics
③ Alkalization of humor (extra-cellular fluid)
→ionization↑ →permeation↓
cell
drug
drug
pH < pH↑
[A-] < [A-] ↑
④ Alkalization of urine→ionization↑
→permeation↓→ drug tubular reabsorption↓
→ excretion↑
blood
urine pH ↑
drug [A-]↑
filtration
pharmacokinetics
2) Filtration (Aqueous diffusion)
The aqueous (hydrophilia) drugs with low
molecular weight (<100-200 daltons) can diffuse
through aqueous pores in membrane without
requiring energy, the diffusion is driven by
concentration gradient. Daltons: the unit of atomic weight
The almost free drugs can be filtrated across
biggish pores of capillaries from or to plasma.
(drug distribution, glomerular filtration and
absorption following im or sc injection).
facilitated transport
pharmacokinetics
3) Facilitated transport
(Carrier-mediated transport)
The passive movement of a drug
across the membrane is facilitated
by its special carrier.
a. saturable process;
b. special binding to the carrier;
c. transport driven by concentration
gradient without consuming
energy.
The drug is released to another side
of the membrane, and the carrier then
returns to original side and state.
Active transport
pharmacokinetics
2. Active transport (up hill)
A drug molecule moves from a side
of membrane relatively low to one of
high concentration with requiring
energy and special carrier.
a. saturable process
b. special binding to the carrier
c. transport against concentration gradient
with consuming energy.
Active transport
pharmacokinetics
For example: penicillin and probenecid
blood→tubule
(high → low)
penicillin
glomerular
filtration
(passive)
blood→tubule
(low → high)
H2O
absorption
Tubule high
osmosis
tubular
secretion
(active)
probenecid competitive
inhibition
(-)
excretion
of penicillin
After glomerular filtration, penicillin undergoes tubular
secretion (an active transport), having a very short half-life
(t1/2=20~30 min). Probenecid having the same active
mechanism can competitively inhibit the tubular secretion
of penicillin. The t1/2 & effects of penicillin are prolonged.
Absorption
pharmacokinetics
Ⅱ.Absorption
The transport of drugs
from administration
locale to bloodstream.
Absorption
pharmacokinetics
1. The routes of absorption
1) im or sc
Absorption of drugs in solution through
filtration from subcutaneous or intramuscular
injection sites to blood is limited mainly by
blood perfusion rate.
Adrenalin: im > sc
why?
a. blood perfusion rate (im > sc)
b. adrenalin ┌ α↑→vesseel↑(subcutaneous) → perfusion↓
└β↑→vesseel↓(skeletal muscle) →perfusion ↑
Absorption
2) po (per oral)
pharmacokinetics
What about weak acids?
Drugs are absorbed in gastrointestinal tract
through lipid diffusion. The absorption takes
place mainly in the upper small intestine.
gastric mucosa
small intestine mucosa
First-pass elimination: The extensive
gastrointestinal and hepatic metabolism may
occur before the drugs are absorbed into
systemic circulation when oral administration
of drugs.
Absorption
pharmacokinetics
3) Sublingual or rectal administration
Absorption properties of the administration
a. incomplete and irregular absorption;
b. without or less First-pass elimination.
For example
Nitroglycerin given sublingually bypasses liver
and enters the superior vena cava and, in turn,
perfuses the coronary and systemic blood vessel,
therefore it is immediately effective to relive
patients with angina pectoris.
Absorption
pharmacokinetics
2. Bioavailability (F)
F is the paramete judging the extent and rate of drug
absorption following extravascular administration (like
orally).
A (drug amounts in body)
F ＝───────────── ×100%
D (administered dose)
F could be the absolute value between of extravascular
and intravascular administration, or relative value
between of standard preparation and test preparation
(pharmaceutical products).
C
Cmax
AUC: area under C-T curve
AUC
Tmax
T
Absorption
pharmacokinetics
AUC (extravascular administration)
F (absolute)＝───────────────── ×100%
AUC (intravenous administration)
judging availability of different routes or administrations
AUC (test preparation)
F (relative) ＝──────────────×100%
AUC (standard preparation)
judging qualification of availability of different products in the same
administration (same route and dose).
C
C
iv
standard
im
test
po
T
T
Distribution
pharmacokinetics
pharmacokinetics
Ⅲ.Distribution
The transport of drugs from
bloodstream to various organs and
tissues, or to different physical
compartments of body.
Distribution
pharmacokinetics
1. Compartments
According to perfusion rate of drugs
to various organs and tissues, body
could abstractly be divided into one, two
or more parts (one compartment model,
two compartments model, three…).
Distribution
1) One compartment model
Drugs within the model are assumed to be
distributed only to the organs with high blood
flow and rapid uniform (brain, heart, liver,
kidneys, lungs, active muscle, …). The C-T
curve have one phase: elimination phase.
The distribution is too rapid to be found in
the C-T curve..
C
C
elimination
phase
Intravenous
injection
elimination
phase
T
extravascular
injection
T
drug
Ka
Ke
。
。
Distribution
dC
  KC
dt
drug
buret
differential equation
Ke
C
Co
exponential
curve
C  C0 e
1/2
1/4
Ke
。
。
logC
 Kt
exponential equation
t1/2
t1/2
T
logC0
Y
=
a
+
logC  logC 0 
T
K
b xt
2.303
straight equation
Distribution
pharmacokinetics
2) Two compartments model
Drugs are not only distributed to the organs or
tissues with rich blood perfusion (central
compartment), but also to that with low blood flow
(peripheral compartment: fat, skin, bone, resting
muscle). The C-T curve have two phases or rates:
a. The distribution rate (alpha half-life, t1/2α).
b. The elimination rate (beta half-life, t1/2β).
Distribution
pharmacokinetics
central
peripheral
K1
Ka
Ke
K2
C
buret
α
distribution
α
β
Ct＝CAe-kαt＋CBe-kβt
β
T
diphasic exponential equation
。
。
elimination
Distribution
pharmacokinetics
2. Apparent volume of distribution (Vd)
Vd relates the amount of drug in the body (A) to
the drug plasma concentration (C), used for
judging drug's distribution range (L).
total amount of drug in body, A(mg)
Vd(L)＝──────────────────── ＝──
concentration of drug in plasma, C(mg/L)
F.D
C
According to the drug plasma concentration,
the amount of drug in the body should be solved
in apparent volume of body fluid.
Distribution
pharmacokinetics
3. Factors influencing distribution
1) drug-plasma protein binding
moving balance
free drug＋plasma
binding drug
(active form)
(inactive storage form)
small particle
large particle
→rapid filtration
→ no filtration
→rapid distribution → → no distribution →
┌ action
┌no action
└elimination
└no elimination
(metabolism & excretion)
Characters of binding to plasma
a. saturability 5mg…15mg…20mg…22.5mg→toxication
Dose↑↑→binding rate↓→free drug↑
malnutrition
liver dysfunction
renal dysfunction
b. nonselective binding
binding
rate↓
Plasmaalbumin↓
binding
rate↓
free
drug↑
free
drug↑
Warfarin (anticoagulant)
A 98% (2%) ┅ ┅ ┅ ┅ ┅→94% (6%) →effect (toxicity)↑↑→bleeding
4%↓
B 92% (8%) ┅ ┅ ┅ ┅ ┅→88% (12%) →
Phenylbutazone (anti-inflammatory drug)
Distribution
pharmacokinetics
2) Barrier: blood-brain barrier, placental barrier
a. less ionized drug & small particle→permeable
b. inflammation→permeable
3) active transport→tissues concentration↑
iodium
active transport
thyroid
4) regional blood flow
central compartment > peripheral compartment
Biotransformation
pharmacokinetics
Ⅳ.Biotransformation
mainly in the liver
hepatic microsomal mixed function oxidase system
1. two phases
Phase 1
Prodrugs
oxidation
reduction
drug activity↓
hydrolysis
Phase 2
conjugation
with glycuronic acid
and acetyl…..
activation
inactivation
(effects↓toxicity↓)
toxicity↓
binding to plasma↓
more polar
excretion↑
Biotransformation
pharmacokinetics
2. Factors affecting drug metabolism
1) drugs
enzyme inducer
activity of enzyme↑
chlorpromazine
phenobarbital
tolerance (dosage↑)
enzyme inhibiter
phenylbutazone
chloromycetin
activity of enzyme↓
hypersensitivity (dosage↓)
Biotransformation
2) Pharmacogenetics
pharmacokinetics
hereditary variation
in handling of drugs
For example:
*Deficiency in activity of acetylase results
peripheral neuritis from isoniazid;
*Absence of glucose-6-phosphate dehydrogenase
(G-6-PD) results hemolytic anemia from some
drugs
sulfonamides
vitamin K (antihemorrhagic)
primaquine (antimalarial agent)
phenacetin (antipyretic analgesic)
broad beans.
absence of
G-6-PD
Hemolytic
anemia &
jaundice
Biotransformation
pharmacokinetics
age sex weight sport…
3) Physiological factors
newborn
Infant
elder
liver function↓
renal function↓
deficiency of
drug elimination
effects ↑
drug toxicity↑
For example:
chloromycetin
newborn
↓
gray syndrome
prohibition
Circulatory failure
elder
many drugs
↓
toxicity↑
dosage↓
Biotransformation
pharmacokinetics
4) pathological condition
hepatic
disease
enzyme
production↓
drug
metabolism↓
plasma
production↓
renal
dysfunction
plasma
loss↑
plasma binding↓
→free drug↑
hypersensitivity
pharmacokinetics
Ⅴ.Excretion of drugs
Drugs and their metabolites in
circulation
are
excreted
by
kidneys, bile, milk, sweat and
lungs.
excretion
pharmacokinetics
tubular secretion
1. Renal excretion
tubular reabsorption
Plasma (Drugs & metabolites)
glomerular filtration
tubular water reabsorption
hyperosmosis in renal tubules
Bicarbonate?
Penicillin?
tubular reabsorption
tubular secretion
(lipid-solubility)
(active diffusion)
Drug excretion↓
(tubule→blood)
Drug excretion↑
(blood→tubule)
Probenecid?
excretion
pharmacokinetics
2. Excretion in bile
Plasma
(drug)
liver
active transport
bile
Hepato-enteric
circulation
portal vein
intestine
prolongation of half-life
 high concentration in bile
PO

Beneficial for antiinflammatory
of cholecystitis
（erythrocin）
Excretion
Exclusion
excretion
pharmacokinetics
3. Excretion in milk
weak alkaline drugs
(morphine, atropine)
effects↑
reactions
in infant
If the mother was the addict,
what would be resulted?
nursing
mother
concentrations
in breast milk↑
dissolved
in milk↑
lactiferous
Ducts milk
(low pH)
reabsorption 
High-lipide
soluble drugs
(sodium pentothal)
Kinetics
pharmacokinetics
Ⅵ.Kinetics and rate process
Kinetics
model
2 compartment
1 compartment
drug
K12
drug
K
K
Differental
equation
dC
  KC
dt
K 21
dC C
  KCC  K 12 C C  K 21C P
dt
dC P
  K 21C P  K 12 C C
dt
Kinetics
pharmacokinetics
1 compartment
Exponent
equation
C  C0 e
2 compartments
C  Ae
 Kt
  t
α
C
C
 Be
  t
β
T
Linear
equation
T
logC
logC
Semi-logarithmic
equation
K
logC  logC 0 
t
2.303
T
A
α
β
B
T

log(C - Be )  logA t
2.303

logC  logB 
t
2.303
-  .t
Elimination
pharmacokinetics
1. Elimination of drugs
Drugs and their metabolites
are eliminated from the body
by excretion and metabolism
with decrease of drug blood
concentration.
1st-order
0-order
0
1
2
100
50
25
1000 900 800
3
4
5
C
Michaelis-Menten
kinetics
T
……
9
10
11
12
……
100
50
25
12.5
12.5 6.25 3.125
700
600
500
non-linear kinetics
Michaelis-Menten kinetics
high dose: 0-order
low dose: 1st-order
Elimination
pharmacokinetics
1) First-order kinetic
All most drugs
Blood concentration of drug is reduced in
equal rate or in constant half-life (t1/2). The
eliminated rate is direct ratio with blood
concentration of a drug.
C
dC
1
  KC
dt
one compartment
t1/2
T
dC
  KC
dt
Exponent=1
2) Zero-order kinetic
Blood concentration of drug is reduced in
equal amount or eliminated in continuant shorten
half-life (t1/2).
dC
 K 0 C 0
dt
C
dC
 K 0
dt
T
Exponent=0
3) non-linear kinetics
Michaelis-Menten kinetics
Low dose→ 1st order
Overdose→ zero order
salicylic acid, phenytoin, alcohol
C
aspirin
Low
dose
1st order
kinetics
Large
dose
Urine pH↓→reabsorption↑
t1/2=2-3 h
zero order
kinetics
C
first
T
t1/2=15-30 h
zero
T
Elimination
pharmacokinetics
4) Half-life of drug (t1/2)
The half-life (t1/2) is the time taked to
decrease the drug plasma concentration by
one-half (50%) during elimination.

It is considered that drugs are almost (97%)
eliminated after 5 t1/2.

1st-order
0
1
2
3
4
5
6
100
50
25
12.5
6.25
3.125
1.563
Elimination
pharmacokinetics
C
C
iv
1st-order
po
T1/2
constant
of a drug
T
T1/2
Relation to
drug character
t1/2
Individual
variation
No relation to
Relation to
body condition
T1/2
T
lipid-solubility,
size of particle,
molecular structure
drug interaction
Kidneys
Liver
……
concentration of drug (therapeutic dose)
way of administration
Steady state
pharmacokinetics
2. Steady state concentration (Css)
When given at a regular interval, a drug plasma
concentration approximately could reach a
plateau after 5 t1/2.
0
dose
amount
100
3
4
5
6
…
100 100
100
100
100
100
…
50
87.5 93.5
96.9
98.43
…
1
2
75
Steady state
pharmacokinetics
1) Level of Css relates to:
* dose ↑→Css↑
* interval shorten → wave of Css ↓
intravenous drip→smooth concentration curves.
（the most effective and safe administration)
2) Time to reach Css relates to:
* When a drug is given at a regular interval, its Css could
reached after 5 t1/2;
* loading dose (first dose↑) →reaching Css rapidly
When the regular interval is t1/2 and loading dose is
double，Css can be reached immediately in intravenous
injection.
Steady state
pharmacokinetics
Steady state concentration
T1/2
0
1
2
3
4
5…
n
100
100
100
100
100
50
75
87.5
93.5
200
200
200
100
150
175
187.5 193.8… 200
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100…
first -order
A. dose
amount
B. dose
200
amount
C. dose
200
amount
200
100
96.9…
200
zero -order
dose
amount
100
50
100
150
200
100
250…
Steady state
C
2D-D
pharmacokinetics
C
D
ivd
93.8%
97%
87.5%
75%
50%
T
1st-order
T
0-order
PHARMACOLOGIC PRINCIPLES
CHAPTER 4
Impact factor
to pharmacodynamics and
pharmacokinetics
Impact factor
Drug
Impact factor
.
Structure
Polar, pKa
Solubility
Dosage form
Product No
PK
drug
Administration
Dosage
Route
Time, Interval
Drug interaction
Repeat use
Withdraw
PD
Physical
sex
age
weight
Mentality
Illness
Heredity
living custom
Individual
variation
body
The end of
PHARMACOLOGIC
PRINCIPLES