PK introduction-2 2021.pdfPK introduction-2 2021.pdf

Chia-Jung Lee 2021.10.20
1
Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs
Pharmacokinetics of
Traditional Chinese Medicine

What is Drug discovery & Development
2

Development of Western medicine vs
Traditional Chinese medicine
Randomized
controlled
double blind
studies
In vitro research
Animal research
Idea, Editorials, Opinions
Case reports
Case series
Case control studies
Control studies
RCDBS
SRM
Systematic reviews
and Meta-analysis
Clinical
Experience
…
4
Western medicine
…
…
Preclinical Study
New drug candidate
Clinical Study
Phase I, II, III

Drug development
症通論描述西醫病名 ICD-9 中醫病名中醫概論西醫概論
疔
皮膚或皮下組織形成毛囊性炎性丘
疹，感覺搔癢，繼以疼痛，隨著膿
成熟，自然潰破，留下瘢痕。可發
生於全身各部位。
痤瘡
7060
7061
肺風粉刺
面皰
《醫宗金鑑》外科心法卷六十五》曰“肺風粉刺肺經熱，
面鼻疙瘩赤腫痛，破出粉汁或結屑”，可用外用顛倒散。
《外科正宗》肺風粉刺酒糟鼻中指出本病的病因是“血
熱鬱熱不散所致”。
痤瘡是一種毛囊與皮脂腺的慢性炎症性皮膚病，
好發於顏面，胸背部多發於青春期男女，常伴
有皮脂溢出，青春期過後，大多能自癒或減輕。
O
O
OH
HO
OH
OH
HO
HO
HO
HO
OH
O
HO
O
O
O
O
O
O
O
O
OH
O O
OH
OH
OH
HO
HO
HO
New Drug
Candidate
PGE
2
Production
(pg/ml)
0
200
400
600
800
1000
P.A. (100 g/ml) - + + + +
+
Compound (100 M) - - 1 2 4
3
** **
**
0
20
40
60
80
100
120
1 2 3 4
Compound (g/ml)
25 50 25 50 25 50 25 50
Testosterone (10 g/ml) - + - + - + - + - + - + - + - +
Cell
vialibity
(%)
- +
0 h
24 h
48 h
1
0
PG mg/site
5
1
0
.
1
(
A
)
(
B
)
(
C
)
(
D
)
(
E
)
(
F
)
b
a a
b
400x
5

6
Drug discovery
Drug dose
Ingestion
Absorption
Distribution
(plasma concentration)
Metabolism
Excretion
Pharmacokinetics Pharmacodynamics
Target organ
Drug effects &
side effects

Pharmacokinetic
Nat Rev Cancer. 2005, 5: 47-58.

General Information
• The first stage for the drugs to reach to their
target organs is known as “absorption”.
• In fact, the absorption is the transportation of the
drug across the biological membranes
• There are different mechanisms for a drug to be transported across a
biological membrane:
✓ Passive (simple) diffusion
✓ Active transport
✓ Pinocytosis
✓ Facilitated diffusion
9

Simple (passive) diffusion
• The major role for the transportation of the drugs across the cell
membrane.
• The substances move across a membrane according to a concentration
gradient.
• No energy is required.
• There is no special transport (carrier) protein.
• No saturation.
• The concentration gradient and the lipid solubility of the drug are the
two main factors that determine the diffusion rate (speed) of the drug.
• Molecular weight of the high lipophilic drugs is not important as much as in
the drugs that are soluble in water, BUT MW OVER 1000 is generally
restrictive!!!
• The simple diffusion of the drugs with high solubility in water occurs
via the aqueous pores found on the cell membrane (i.e. caffeine, ascorbic
acid, acetylsalicylic acid, nicotinamide).
10

Active transport
• The transportation of the drug molecules across the cell membrane
against a concentration or an electrochemical gradient.
• It requires energy (ATP) and a special transporter (carrier) protein.
• There is «transport maximum» for the substances (the rate of active
transport depends on the drug concentration in the enviroment).
• Ooccurs by the carrier proteins.
• Net flux of drug molecules is from the high concentration to low
concentration.
11

Factors that affect the absorption of the
drugs
A) DRUG-RELATED FACTORS
✥ Molecular size
✥ Lipid solubility
✥ Degree of ionization
✥ Dosage form
✥ Chemical nature (Salt/organic forms,
crystal forms, solvate form etc.)
✥ Particle size
✥ Complex formation
✥ Concentration of the drug
B) SITE of APPLICATION
RELATED FACTORS
Blood flow (at site of application)
Area of absorption
12

Drug Absorption
✥ Routes of Drug Administration
– Oral (per os, p.o.)
– Inhalation
• vapors, gases, smoke
– Mucous membranes
• intranasal (sniffing)
• sublingual
• rectal suppositories
– Injection (parenteral)
• intravenous (IV)
• intramuscular (IM)
• subcutaneous (SC)
• intraperitoneal (IP; nonhumans only)
– Transdermal

Drug Absorption
✥ Local administration
✓ Epidermal (percutaneous)
✓ Intracutaneous
✓ Conjunctival
✓ Intranasal
✓ Intrapleural
✓ Intrauterine
✓ Intracardiac
✓ Intravaginal
✓ Intraarticular
14
✥ Systemic administration
✓ Parenteral route
✓ Into veins** or arteries
✓ Intramuscular
✓ Subcutaneous
✓ Inhalation
✓ Transdermal route
✓ Enteral route
Following IV injection, the effect starts immediately and the bioavailability
is 100%.
Im injection is applied to generally gluteal and deltoid muscles; 5 ml is the
maximum injection volume.
For subcutaneous injections, the injection volume shouldn’t exceed 2 ml.
These drugs should be small particle sized with high lipid-water partition
coefficient.
Transdermal therapeutic systems (TTS, patch) are used generally for
transdermal drug application.
These are absorbed from the skin to circulation to obtain a systemic effect.

Enteral route
✥ The drug is given to GI tract and absorbed from GI tract.
✥ There are 3 ways for enteral route:
✓ Oral
✓ Sublingual
✓ Rectal
✥ This is the most often used administration route of the drugs.
✥ This route is known to be the safest, easiest and the most economic
way of administering drugs.
✥ Drug molecules are mostly absorbed from duodenum, jejunum and
upper ileum.
✥ Disintegration and dissolution are the two main processes for the
oral administered drugs before the absorption process.
✥ The absorption rate and absorption ratio of the orally administered
drugs are closely related with the above two parameters.
15

Oral route
Bioavailability:
✥ “In which extent (rate) the body benefits from the drug” is known as
bioavailability.
✥ For the orally administered drugs, bioavailability (systemic bioavailability) is the
“fraction of unchanged drug that reaches to the systemic circulation
from the administration site (after passing through the liver)”.
➢ First-pass metabolism (pre-systemic elimination):
➢ Examples: propranolol, tricyclic antidepressants,
opioid analgesics like morphine and meperidine, some sex hormones.
16

Bioavailability, F
F
=
A
D
× 100%
Formula
In pharmacology, bioavailability (BA) is a subcategory
of absorption and is the fraction of an administered
dose of unchanged drug that reaches the systemic
circulation, one of the principal pharmacokinetic
properties of drugs.
17

Routes of Drug Administration
✥Oral Drug Administration
– Advantages:
• relatively safe, economical, convenient, practical
– Disadvantages:
• Blood levels are difficult to predict due to multiple
factors that limit absorption.
• Some drugs are destroyed by stomach acids.
• Some drugs irritate the GI system.

✥Advantages of Injection Routes
– Absorption is more rapid than with oral administration.
– Rate of absorption depends on blood flow to particular tissue site
(I.P. > I.M. > S.C.).
✥Advantages specific to I.V. injection
– No absorption involved (inject directly into blood).
– Rate of infusion can be controlled.
– A more accurate prediction of dose is obtained.

✥Disadvantages/Risks of Injection
– A rapid onset of action can be dangerous in
overdosing occurs.
– If administered too fast, heart and respiratory function
could collapse.
– Drugs insoluble in water or dissolved in oily liquids
can not be given I.V.
– Sterile techniques are necessary to avoid the risk of
infection.

Absorption
• Sublingual – rapid
• Transdermal/topical – slow, systemic or local
• Rectal – unpredictable rate
• Inhalation – rapid absorption, local or systemic
• Other: eye, ear, nose, vaginal – most drugs stay
local
• Delayed release delivery systems
– extended-release capsules and tablets
– Depot subcutaneous and IM injections
21
A first course in pharmacokinetics and biopharmaceutics. Biopharmaceutics and Pharmacokinetics website.
http://www.boomer.org/c/pl/index.html. Accessed September 27, 2013.

✥Absorption
22
Pharmacokinetics studies
Routes Of Drug
Administration
Enteral
Parenteral
Oral
Injection Rectal
Respiratory
Topical

Permeation Studies across Cell
Monolayers
Song Q et al. 2014;9 :1:2157—2165
Int. J. Mol. Sci. 2016, 17(7), 1171
N
NCM 460 Cells
Monolayer
NCM 460 cells-
Normal colonic
epithelial cell

Permeation Studies across
Cell Monolayers
28
Fig. 4. General setup of permeability experiments. A) intestinal barrier model using Caco-2 cells in 6-well
plates; B) human monoculture BBB model using hBMEC cells in 24-well plates; C) rat triple co-culture
BBB model using primary rat brain endothelial cells, pericytes and astrocytes in 24-well plates.
In vitro transport studies with kaempferol and its anxiolytic metabolite 4-HPAA in human cell models

29
29
1. brush-border membrane peptidases
2. brush-border membrane amino acid transporters
3. brush-border membrane di- and tripeptide
transporters
4. intracellular peptidases
5. basolateral-membrane amino acid carriers
6. basolateral membrane di- and tripeptide carriers
Intestinal Absorption & Lymphatic absorption

Flow of milky lymph fluid (with syringe suction)
30
ANDREW L. WARSHAW,
Gut, 1972, 13, 66-67
Original surgical procedure
Chen et al., J. Agric. Food Chem. 2010, 58, 546–551

Distribution
✥ Distribution is passage of drug molecules to liquid compartments
and tissues in the body via transportation across the capillary
membrane.
✥ The body fluid compartments and volumes in which the drugs are
distributed:
31

Drug Distribution
✥Cell Membranes
✥Capillaries
– Drug affinities for plasma proteins
• Bound molecules can’t cross capillary walls
✥Blood Brain Barrier
– Tight junctions in capillaries
– Less developed in infants
– Weaker in certain areas, e.g. area postrema in brain stem
– Cerebral trauma can decrease integrity
✥Placenta
– Not a barrier to lipid soluble substances

Distribution
✥ Time from circulation to target tissue: factors are rate (cardiac
output), volume, diffusion model, drug properties.
✥ one compartment model (linear kinetics): drug absorbs and
distributes quickly, ie bolus IV
– molecules less than 10,000 grams/mole diffuse freely through
capillaries
Factors affecting the distribution of drugs:
• Diffusion rate
• The affinity of the drug to the tissue components
• Blood flow (perfusion rate)
• Binding to plasma proteins
33

Factors affecting the distribution of
drugs
✥Blood flow (perfusion rate):
✓ There is a positive correlation between the blood flow in
the tissue and the distribution of the drugs.
✓ Kidney, liver, brain and heart have a high perfusion rate
(ml/100 g tissue/min) in which the drugs distribute higher;
✓ Skin, resting skeletal muscle and bone have a low
perfusion rate.
✓ The total concentration of a drug increases faster in well-
perfused organs.
34

Factors affecting the distribution of
drugs
✥Binding to plasma proteins:
✓ The most important protein that binds the drugs in blood is
albumin for most of the drugs.
✓ Especially, the acidic drugs (salicylates, vitamin c,
sulfonamides, barbiturates, penicillin, tetracyclines, warfarin,
probenesid etc.) Are bound to albumin.
✓ Basic drugs (streptomycin, chloramphenicol, digitoxin, coumarin
etc.) Are bound to alpha-1 and alpha-2 acid glycoproteins,
globulins, and alpha and beta lipoproteins.
35

Properties of plasma protein-drug
binding
✥Saturable:
❖One plasma protein can bind a limited number of
drug molecule
✥Non-selective:
❖More than one kind of drug which has different
chemical structures or pharmacological effects
can be bound to the space on plasma protein
✥Reversible:
❖The bonds between the drug and plasma protein
are weak bonds like hydrogen or ionic bonds.
36

Distribution
✥Two compartment model:
– compartment 1
• central circulatory system
• rapidly perfused tissues and organs
– cardiac muscle
– brain
– lungs
– liver
– compartment 2
• peripheral circulatory sys.
• deep organs and tissues
– skeletal muscle
– adipose tissue
– skin
✥
37
Two Compartment
Model
A first course in pharmacokinetics and biopjharmaceutics website anesthesiologist book

Distribution
✥ Three compartment model: drugs dependent on active
transport
– V1 circulation and rapidly perfused tissues
– V2 slowly perfused tissues
– V3 third much slower equilibrium compartment
38
Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

Distribution
❑ Passage of the drugs to CNS:
– A blood-brain barrier exists (except some areas in the brain) which limits the
passage of substances.
– Non-ionized, highly lipophilic, small molecules can pass into the cns and
show their effects.
– Some antibiotics like penicillin can pass through the inflamed blood-brain barrier
while it can’t pass through the healthy one.
❑ Passage of the drugs to fetus:
– Placenta doesn’t form a limiting barrier for the drugs to pass to fetus.
– The factors that play role in simple passive diffusion, effect the passage of drug
molecules to the fetus.
➢ Placental blood flow
➢ Molecular size
➢ Drug solubility in lipids
➢ Fetal ph (ion trapping): fetal plasma ph: 7.0 to 7.2; ph of maternal plasma:
7.4, so according to the ion trapping rules, weak basic drugs tend to
accumulate in fetal plasma compared to maternal plasma.
39

Volume of Disribution
Volume of distribution = amount of drug administered (dose) (mg) /
concentration of drug in plasma (mg/ml)
✥ Most of the times, volume of distribution calculated in this way is not equal
to the real total volume of physiological liquid compartments in which the
drug is distributed.
✥ So it may be called as “apparent volume of distribution (vd)”.
✥ Following a single-dose intravenous administration of a drug, log plasma
concentration-time graph is plotted according to the values of plasma
concentration taken at particular time points.
✥ Then the formula is:
Volume of distribution (vd) = dose (iv) / C0’
✥ Also, you can calculate the volume of distribution from the same graph by
using AUC (area under curve) and ke (rate constant for elimination) like:
Volume of distribution (vd) = dose (iv) / (AUC x ke)
40

✥Distribution
– Plasma concentration
– Target organ concentration
– Factors affecting on protein Binding
41

Microdialysis Advantage:
• Continuous sampling
• Dynamic observation
• Quantitative analysis
• Sampling small
• Tissue damage light
• Measure low molecular weight
Defect:
• Salt and the presence of
small molecules, will
seriously affect the sample
molecule
Microdialysis

Semi-permeable
membrane
perfusate
probe
Dorsal hippocampus
(L: ± 4.6, A: −5.6 and V: +4.6)
Striatum
(L: ± 3, A: −7.5 and V: +0.2)
Microdialysis & liquid chromatographic–mass
spectrometric (LC-MS-MS)
43
Stereotaxic apparatus anesthetized Free moving
LC-MS/MS
Liver Kidney
Plasma concentration

◼Pharmacokinetics and herb-drug interaction
◼ Uncaria rhynchophylla (Gou-Teng)
• Blood and brain distribution
• Hypertension drug interaction
44
A: acetylcholine system
B: monoamines system

46
Flow-through
-dialysis Probe
Femoral vein
injection
Direction
& Route
Bile Microdialysis for Hepatobiliary
Excretion Study
46
Tsai et al., 2002

Metabolism
• Metabolism starts as soon as drug
reaches enzymes capable of
metabolizing.
• liver
• kidney
• no metabolism
• proteolytic catabolism
• large protein biotech
• drugs
47
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf
https://elcaminogmi.dnadirect.com/grc/patient-site/psychiatric-drug-response/what-affects-psychiatric-drug-response.html

• First-pass metabolism
occurs before drug reaches
circulation
drugs with larger oral vs IV dose
–propranolol
–morphine
• Prodrugs
enhanced bioavailability
avoids first-pass
metabolism
Metabolism
48
http://epharmacology.hubpages.com/hub/Pharmacological-Effects-Prodrugs-Definition-Examples-and-Sources-of-Drug-Information

Metabolism
✥CYP450 – cytochrome P450
enzyme system
– liver and intestines most
common sites
– P450 enzymes can be
inhibited (slowed), induced
(sped up)
– drugs often compete for same
enzyme subgroup
49
http://www.boomer.org/c/p4/c07/c0702.html
http://www.thebody.com/content/art875.html

Geraniol Metabolism
Phase 1 enzymatic reaction
✥ parent drug is converted
into more soluble
excretable agents by
introduction or unmasking
of functional component.
✥ Includes: oxidation,
reduction and hydrolysis
✥ CYP enzymes bio
transforms 75% of all
human drugs

Geraniol Metabolism
Phase 11 enzymatic activity
✥ Combine drugs with
endogenous substrates
like glucuronic acid,
sulphuric acid, amino acid
or acetic acid
✥ Conjugation reaction

Oxidation reactions
✥ Oxidation reactions are performed mostly*** by the enzymes in liver
(hepatocytes) which are localized in the endoplasmic reticulum in
microsomal fractions.
✥ These enzymes are cytochrome p450 mixed-functional
oxidases.
✥ For the oxidation reactions, also molecular oxygen (o2) and nadph
are required.
✥ Some special characteristics of microsomal p450 enzyme
system:
✓ They are located in hepatic microsomes.
✓ The substrate specificity is low.
✓ Shows high affinity to high lipophilic molecules.
✓ Nadph and molecular oxygen (o2) is required for its activity.

Hydrolysis reactions
✥ A group is separated from the drug molecule, or drug
molecule is broken down into two smaller molecules.
Esterase (hydrolysis)
reactions
Acetylcholine esterase,
pseudo choline esterase,
amidase
Decarboxylation Decarboxylases
Glycoside hydrolysis β-glycosidases
O-dealkylation
N-dealkylation
S-dealkylation

Factors that affect the
biotransformation of drugs
1. Induction or inhibition of microsomal enzymes
2. Genetic differences
3. Age
4. Gender
5. Liver diseases
6. Environmental factors

Environmental factors
✥Inhibition of microsomal enzymes can
occur with;
✓Carbon monoxide inhibits the microsomal
enzymes.
✓Grapefruit juice (some flavonoids in grapefruit
juice can inhibit CYP3A4)

Overview
❑Renal excretion
❑Biliary excretion
❑Excretion from the lungs
❑Excretion into breast milk
❑Artificial excretion ways

Metabolism
✥Half-life: t1/2
– describes rate drug disappears from plasma
– helpful with dosing parameters
– exponential decline
• Example: drug with 11 minute t1/2
– 1st 11 minutes concentration drops to 50%
– 2nd 11 minutes concentration drops to 25%
– 3rd 11 minutes concentration drops to 12.5%
– 4th 11 minutes concentration drops to 6.25%
✥Not to be confused with duration of action
58
Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org

DDI study
1. Stock microsomes 20 mg/mL
– 171 µL of 100 mM phosphate buffer (pH 7.4)
– 2 uL 100X Test article in DMSO (final concentration 5, 10, 15, 20 μM)
– 2 uL 100X inhibitors (100X mean Ki)
– 10 uL of 20 mg/mL microsomes (final concentration 1 mg/mL)
2. Pre-incubate microsomes, buffer, and test article in water bath for 5 min.
3. Initiate the reactions with the addition of 10 μL 20 mM NADPH.
4. Incubate up to 60 min at 37°C with gentle agitation.

✥Metabolized in the liver by CYP 450 enzymes
➢ Converted to inactive metabolite; 6α-3’-P-dihyroxypaclitaxel
✥CYP 450 enzymes inhibitors alters paclitaxel
metabolism
➢ Lead to increased efficacy or toxicity of paclitaxel
Paclitaxel metabolism
Mukai, Senda et al. 2015

✥Paclitaxel has high affinity for Pgp efflux
transporters
Efflux of Paclitaxel by P-glycoprotein
Jang, Wientjes et al. 2001

Human Liver Microsomal study
✥ Group 1 Calibration Curve
✥ Group 2 Taxel incubation 60 min
✥ Group 3 Taxel incubation 120 min
✥ Group 4 Taxel + 香砂 incubation 60 min
✥ Group 5 Taxel + 香砂 incubation 120 min
✥ Group 6香砂 +HLM incubation 30 min → add Taxel → incubation 60 min
✥ Group 7香砂 +HLM incubation 30 min → add Taxel → incubation 120 min
62

Enzymatic Activities in Mice Liver

Non-glycosylated and Glycosylated flavones
Journal of Food and Nutrition Research 47(2008)151-162
Polish Journal of Microbiology 65(2016)137–151
⚫ Application of flavonoids is limited by their poor water-solubility and short time spent in
intestine, which result in low absorption.
⚫ Gycosylated forms of flavonoids, which usually are better soluble, more stable, and
more functional compared to their aglycones.

i.v (3 mg/kg) p.o (100 mg/kg)
• The systemic exposure to eupatilin by either p.o or i.v administration, the absolute highest
bioavailability (F = 2.70%) was comparable to that of a published study (3.86%).
• The higher systemic exposure and longer t1/2 of E-7-G than that of eupatilin could allow E-7-G to better
support the substitute effect of eupatilin.

Tissue distribution of eupatilin and E-7-G in rats
Distribution of eupatilin (E) and E-7-G (F) in rats after intravenous administration of
eupatilin(n = 5).
• The immediate generated E-7-G was also quickly distributed to these tissues and
exhibited a similar pattern to that of the parent form, which probably explains the large
expression of UGTs in the above tissues.
• The high distribution of eupatilin and especially E-7-G in the small intestine when
intravenous administration is used explains this observation.
Eupatilin E-7-G

Excretion
✥Most common routes
– kidney
• diffusion
• active transport
– liver
• through bile duct into feces
✥Enterohepatic recycling
– drug excreted into feces
– metabolized in intestine and reabsorbed
• oral contraceptives
69

Excretion
✥Kidney
– some drugs pass through by diffusion (passive transport)
– some drugs pass by active transport into kidney tubule
– many renally excreted drugs require dose adjustments
based on renal function
• creatinine clearance (CrCl) or glomerular filtration rate (GFR) used
to evaluate renal function
– declines naturally with age
– helpful online calculator: www.globalrph.com
70

Biliary excretion
✥ These substances are generally
secreted into the biliary ducts from the
hepatocytes by active transport and
finally they are drained into the
intestines.
✥ Especially, highly ionized polar
compounds (conjugation products) can
be secreted into the bile in remarkable
amounts.
✥ The most suitable molecular weight for
the drugs to be secreted into the bile is
approximately 500 KD.

Excretion
✥Hemodialysis
– small molecules
– water soluble drugs
– drugs with low protein binding
✥Lungs
– excretion of gases
– anesthesia
– alcohol
73
http://www.medbroadcast.com/test_and
_procedure_info_details.asp?TPid=8&Type
=1#.Ukxyuoasim4
Hemodialysis Schematic

Clearance
✥ It can be described as the volume of plasma cleared from the drug per unit
time (ml/min).
✥ Total Body Clearance: It is the plasma volume cleared from the drug per
unit time via the elimination of the drug from all biotransformation and
excretion mechanisms in the body.
✥ Renal Clearance: It can be described as the rate of the excretion of a
drug from kidneys. So in other words, renal clearance is the volume of
plasma cleared from the non-metabolized (unchanged) drug via the
excretion by kidneys per minute.
✥ There are four important factors that affect the renal clearance of the drugs:
✓ Plasma protein binding of the drug.
✓ Tubular reabsorption ratio of the drug.
✓ Tubular secretion ratio of the drug.
✓ Glomerular filtration ratio of the drug.

75
• Cmax maximum concentration
• tmax time to maximum concentration
• Duration of action for this hypothetical drug: time above the minimum
effective concentration (MEC)
• Therapeutic range: concentration above MEC but below maximum tolerated
concentration (MTC)
• Area under curve (AUC) is a function of concentration and time that
describes total body exposure to drug
Figure 1. International Journal of Impotence Research website. www.nature.com/ijir/journal/v19/n3/fig_tab/3901522f1.html. Accessed September 27,
2013.
Pharmacokinetic
parameters describing a
typical plasma
concentration time profile
after an oral administration.

Enterohepatic recirculation
76

77
Hepato-duodenal shunt model
77
-dialysis
Bile duct cannula
Donor-rat
Femoral
vein
Recipient-rat
The bile duct of the donor rat was
cannulated with a PE tubing and
the other end of the tubing was
inserted into the duodenum of
the recipient rat.
To balance the bile fluid losses in
the donor rat and gains in the
recipient rat, the bile duct of the
recipient rat was cannulated
back to the donor rat
If the drug was detected in the
recipient rat. It suggests that the
drug come from the bile duct of
donor rat by biliary excretion and
enterohepatic circulation.
-dialysis
Tsai et al., 2000

80
Estimate enterohepatic circulation
26.9/1508.9 = 1.8 %
47.5/972.1 = 4.9 %

✥Elimination
81
Elimination
Drug Metabolism
(Biotransformation)
Excretion
(Feces,urine)

Thank you for your attention
82

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