Transcript T 1/2

pharmacokinetics
Department of pharmacology
Yang Fang-ju (杨芳矩)
2010.3
Section 1 drug process in the body
 1. classification of drug process in
the body
 It includes absorption, distribution,
metabolism, excretion.
 Metabolism and excretion are called
elimination.
tissue, cells
dissociation
bind
Blood plasma
absorption
Dissociated drug
Bound drug
excretion
metabolite
biotransformation
Process of drugs in the body

2. transportation of drugs across membranes
 The absorption, distribution, biotransformation,
and excretion of a drug all involve its passage
across cell membranes.
 Transported model:
 ⑴Passive diffusion
 It transports along a concentration gradient
 ※ It needs not metabolic energy
 ※ it is usually determined by its pKa, lipidwater partition coefficient, molecular weigh,
and pH gradient in solution.
① lipid soluble diffusion (simple diffusion)
 The nonionized molecules are usually lipid
soluble and can diffuse across the cell
membrane.
 ② Filtration through pores
 Hydrophilic lipid-insoluble substances can
cross membranes through water-filled pores.
 ③ Passive facilitated diffusion
 This flows the concentration gradient but
dose not obey simple diffusion lows. It is
believed to involve a carrier mechanism.

(2) Active transport
 This is a process in which a solute
moves across membrane against an
electrochemical gradient. Either against
a concentration gradient or, if the
solution is charged.
 ※ It transports against a concentration
gradient.
 ※ It needs metabolic energy
 ※ It involves carrier mechanism, so it
can become saturated
 ※ It shows specificity for a particular
type of chemical structure

 3.
Ionicity influence lipid-soluble
diffusion
 the
degree of dissociation of the
drugs can express as
Handerson-Hasselbalch equation:
weak acids:
HA
weak bases:
H+ + A-
Ka = [ H + ] [A- ]
[ HA ]
H+ + B
Ka = [ H +] [ B- ]
［BH］
-lgKa=-lg[H+]-lg [A-]
[HA]
pka = pH - lg
BH
[A-]
[ HA ]
A- ]
That：pH - pka = lg [[HA
]
-lgKa=-lg[H+]-lg [B]
[BH+]
pka = pH - lg
[B]
[ BH+ ]
pka - pH = lg [ BH ]
[B]
10 pH -pka = [ A- ]
[ HA ]
When pH = pka,
10 pka -pH = [ HA ]
[B]
when pH = pka,
[ HA ] = [ A ]
[ B ] = [ BH ]
10 pH -pka = [ A- ]
10 pka -pH = [ HA ]
[ HA ]
[B]
When pH = pka,
when pH = pka,
[ HA ] = [ A ]
[ B ] = [ BH ]
3. Process of drugs in the body
 (1) absorption
 ①absorption of drugs from alimentary
canal
 oral ingestion is the route of most
drugs administration.
 Absorption
from
mouth:
gastrointestinal tract epithelium
in
blood
 portal circulation
liver
systemic
circulation

first pass elimination:
drug concentration in the blood is declined because
metabolism of drugs as a result of passage through
the liver and intestine when absorption in the
alimentary tract.
 rectal administration:
50%of the drainage of the rectal region bypasses the
portal circulation; thus, the biotransformation of
drugs by the liver is minimized.
It is also useful if the drug induces vomiting, when
given orally or the patient is already vomiting.
② sublingual administration
 Placement under the tongue allows the drug
to diffuse into the capillary network and
therefore to enter the systemic circulation
directly.
 Both the sublingual and the rectal rout
have the additional advantage that they
prevent the destruction of the drug by
intestine and liver enzyme or by low pH in
the stomach.
 parenteral adminstration


intravenous injection
 subcutaneous injection
 intramuscular injection
 intra-arterial injection
 ① pulmonary absorption
 ② transdermal administration
 (2) distribution of drugs
 Factors influence distribution of drugs
redistribution
heart
liver
pseudoequilibrium
brain
fat
①regional blood flow and affinity of
drugs with tissues
 ② physicochemical characteristics
 ③ protein binding
※ the binding is reversible and there is a
dynamic equilibrium between
the bound and unbound forms of a drug.

D
D + P DP
 ※ Bound drug is not effective and serve
as a substantial drug reservoir
※
The
drugs
with
similar
physicochemical
characteristics
compete with each other for the biding
site and result competitive inhibition.

① special barrier
 ※ blood-brain barrier
 ※ placenta barrier
3. biotransformation of drugs
 (1) oxidative reaction
 (2) reductive reaction
 (3) hydrolytic reaction
 (4) counjugation reaction
the hepatic microsomal enzymes:
 It is in the endoplasmic reticulum
therefore often are classified as
microsomal enzymes. These are
primarily cytochrome P450 enzyme
family that is the major catalyst of
drug biotransformation reactions.
Non-specificity
 ※ The activity has some limit, it can
be inhibited or induced competitively
by other drugs interacting with the
same system
 ※ It has large difference in various
individual
 ※ It can be inducted or inhibited by
various drugs
 The hepatic microsomal enzymes
inducers:
The hepatic microsomal enzymes inducers:

The drugs that can increase synthesis and
activity of the hepatic microsomal enzymes. It
leads to an increased rate of biotransformation
and corresponding decreases in the availability
of the parent drug.
The hepatic microsomal enzymes inhibitors:
 The drugs that can decrease synthesis
and activity of the hepatic microsomal
enzymes.

Inhibition of drug biotransformation
enzymes results in elevated levels of the
parent drug, prolonged pharmacological
effects, and an increased incidence of
drug-induced toxicity.

Competition between two or more drugs
for the active site of the same enzyme may
lead to a decrease in the metabolism of
one of these agents, depending on the
relative concentrations of each substrate
and their affinities for the enzyme.

4 Excretion of drugs
drugs are eliminated from the body either
unchanged or as metablites.
Excretory organs, the lung excluded, eliminate
polar compounds more efficiently than
substances with high lipid solubility.
The kidney is the most important organ for
elimination of drugs and their metabolite.
(1) Renal excretion
 Excretion of drugs and metabolites in
the urine involves three processes:
glomerular filtration, active tubular
secretion,
and
passive
tubular
reabsorption.
(2) Biliary and fecal excretion
 Hepato-enteral circulation: the
metabolites of drugs formed in the
liver are excreted into the intestinal
tract in the bile and are reabsorbed
from the intestine.
(3) Excretion by other routes
 The metabolites of drugs are also
excreted into sweat, saliva, tears, and
breast milk.
 Although excretion into hair and skin
also is quantitatively unimportant,
sensitive methods of detection of toxic
metals in these tissues have forensic
significance.
Section 2. time process of drug
concentration change in the body
1.time–concentration relationship and timeresponse relationship
 Drug concentration time curve (C-T
curve): the curve is obtained from
concentration or logarithmic
concentration for the ordinate and from
time for the abscissa.
(1) drug absorption and C-T curve
 ① peak concentration (Cmax)
 ② peak time (Tmax)
 ③ effective period
 ④ area under the curve (AUC)
⑤ bioavailability
 The amount of the drug that reaches the
systemic circulation can be expressed as a
fraction of the dose F, which often is called
bioavailability.
AUC(parenteral administration)
 F=
×100%

AUC(intravenous administration)
AUC(trial drug)
 F= AUC(standard drug)×100%

it is important to distinguish between the rate
and extent of drug absorption and the amount
that ultimately reaches the systemic
circulation.
(1) distribution of the drug and C-T curve
 ① one-compartment model

intravenous administration
drug
Central compartment
elimination



Figure. plasma
concentration-time
curves following
intravenous
administration of a
drug(500mg) to a
70kg man.

②

intravenous administration
drug

two-compartment model
central compartment
k21
elimination
k12 distribution

external compartment

It indicates that, in fact, the drug follows multiexponential kinetics.
① volume of distribution (Vd)
 the volume of distribution (V) relates the
amount of drug in the body to the
concentration of drug (C) in the blood or
plasma, depending upon the fluid measured

This volume dose not necessarily refer to an
identifiable physiological volume, but merely
to the fluid volume that would be required to
contain all of the drug in the body at the same
concentration as in the blood or plasma.








Vd = FD
C
F: bioavailability, D: drug dose,
C: plasma concentration of drug
Section 3 eliminated kinetics of drug
1. elimination of drug and C-T curve
① half-life (T1/2):
the time it takes for the plasma concentration or the
amount of drug in the body to be reduced by 50%.
According to first-order kinetics:
C = C0 e-ket, C/C0=e-ket
takes the nature logarithm:
 Ln(C/C0)=-ket, t=ln(C/C0)/-k
 when t = 1/2,
 t1/2=ln1/2/-k=2.303/-k=0.693/k
 ∴ t1/2= 0.693/k
 The elimination in various half life is:
 At = A0e-kt = A0e-0.693/t1/2×n×t1/2 = A0e-0.693n
=A0 (0.5)n = A0 (1/2)n
 When n = 5, At = 3%A0
 it shows that drug is almost eliminated
from the body.

if the drug repeated administration at
intervals equal to its elimination half life time,
the steady state concentration (Css) is
attained after approximately 5 half life times.
 The calculated equation of accumulation
volume in various half life is:
 At = A0(1-e-kt) = A0(1-e0.693/t1/2×t1/2×n)
 = A0(1-e-0.693n) = A0[1-(0.5)n] = A0[1-(1/2)n]

2. first -order kinetic elimination
 (1) drug is cleared in an exponential
manner and eliminated in a constant
fraction;
 (2) T1/2 is constant,
 T1/2 = 0.693/K.
 the steady state concentration (Css)
or almost elimination of the drug in
the body is attained after
approximately 5 half life times.
3. zero -order kinetic elimination
 drug is eliminated in a constant
volume manner
 T1/2 is not constant, T1/2 = 0.5/C0
 according to the equation:
 dc/dt=-kC0,
 C = C0 – kt
C0-C

T=

∴T1/2 = 0.5C0/k
k
,
t1/2 =
C0-1/2C0
k
= 0.5C0/k
1.0
10
0.9
9
0.8
恒量消除
恒比消除
8
浓 0.7
度
0.6
7
(Mg/ml )
0.5
5
0.4
4
0.3
3
0.2
2
0.1
1
0
0
6
1 2 3 4
5
6 7
8
1
2
3
4
5
6
7
10
10
9
9
Mg/ml
恒比消除
8
恒量消除
8
7
7
对 6
数 5
尺
度 4
6
3
3
2
2
0
0
5
4
1 2
3
4 5 6
(小时)
7 8
1 2 3
4 5 6
(小时)
7
8
2. repetitive doses and C-T curve
 commonly
used
administration
scheme
 (1)
Repetitive administration in equal
doses and at regular interval
 (2)
administration scheme of loading
dose and maintenance doses
① Loading dose
 A “loading dose” is one or series of
doses that may be given at the onset
of therapy with the aim of achieving
the target concentration rapidly.

The appropriate magnitude for the
loading dose is:







Dl = Dm/(1-e-kt)
if: t = t1/2, then:
Dl =Dm/1-e-0.693t1/2÷t1/2 =Dm/1-e0.693
= Dm/0.5= 2Dm
A loading dose is chosen which is twice the
maintenance dose at first and the following
maintenance dose interval is equal to T1/2 of
the drug, the steady state blood concentration
(Css) should be established from the
beginning.
When the interval time of administration
τ= T1/2,
Css = (F×dose)÷(Cl×T)
In most clinical situations, drugs are
administered in a series of repetitive
doses or as a continuous infusion in
order to maintain a steady state
concentration of drug in plasma within a
given therapeutic range.
 To maintain the chosen steady state or
target concentration, the rate of drug
administration is adjusted such that the
rate of input equals the rate of loss.
 Dm = (MTC – MEC)×Vd

loading dose administration scheme of
intravenous progression dripping injection
in even rate:
 Css =R(1-e-ket)/CL
 When beginning: t = 0, e-ket =1, (1-eket) = 0,
 when arrives in Css, e-ket →0, than (1-eket)→1, C
ss =R/CL
 from CL = Vd﹒k to Css = Css =R/CL:
 Css =R/Vd﹒k
 ∵ k =0.693/k , or 1/k=1.44﹒t1/2 ,
 ∴ Css = R/Vd﹒t1/2/0.693 =R/Vd﹒1.44
