Chapter1 Pharmacokinetics
Chapter1 Pharmacokinetics
Chapter1 Pharmacokinetics
Chapter 1 Pharmacokinetics
1. Drug of choice
2. How much
3. How often
4. For how long
Pharmacokinetics
Absorption
Distribution Elimination
Drug Concentration at
Site of Action
Pharmacodynamics
Pharmacologic Effect
Clinical Response
Toxicity Efficacy
physiological disposition of drugs
absorption
distribution
metabolism (biotransformation)
elimination
100
Drug at absorption site
80
% of dose
60
Metabolites
Drug in body
40
Excreted drug
20
Time
Ⅱ . Movement of drugs in the body
Passive diffusion
Driving force: the concentration gradient across
membrane
Direction: from a region of higher concentration
to a lower one
No carriers, not saturable, low structural
specificity
Vast majority of drugs gain access to the body
by this mechanism
Water-soluble drugs: through an aqueous
channel or pore
Lipid-soluble drugs: solubility in the membrane
Facilitated diffusion
Driving force: specialized transmembrane
carrier proteins, conformational changes
Direction: from a region of higher
concentration to a lower one
Does not need energy, can be saturated
Compounds may compete for the same
carrier---inhibition
Active transport
Driving force: specific carrier proteins
Direction: from a region of lower
concentration to a higher one
Energy-dependent
Saturation kinetics for the carrier
Selective
May be competitively inhibited by other
co-transported substances
Endocytosis and exocytosis
For drugs of exceptionally large size
Endocytosis: engulfment of a drug molecule
by the cell membrane and transport into the
cell by pinching off the drug-filled vesicle.
Eg. Absorption of VitB12
Exocytosis: be used by cells to secrete many
substances by a similar vesicle formation
process. Eg. Release of neurotransmitters
Classification of membrane transport mechanisms
Ionization of Weak Acids and Weak Bases; the
Henderson-Hasselbalch Equation
A very large percentage of the drugs in use are weak acids or weak
bases
A drug of weak acid is best defined as a neutral molecule that can
reversibly dissociate into an anion and a proton
If the pKa of the drug and the pH of the medium are known, the fraction of molecules in
the ionized state can be predicted by means of the Henderson-Hasselbalch equation
the pH of the medium determines the fraction of molecules charged (ionized) versus
uncharged (nonionized)
the lower the pH relative to the pKa, the greater
will be the fraction of drug in the protonated form. Because the
uncharged form is the more lipid-soluble, more of a weak acid will
be in the lipid-soluble form at acid pH, whereas more of a basic
drug will be in the lipid-soluble form at alkaline pH
Ionization of Weak Acids and Weak Bases; the
Henderson-Hasselbalch Equation
Ionization of Weak Acids and Weak Bases; the
Henderson-Hasselbalch Equation
Be clinically important when it is necessary to estimate or alter
the partition of drugs between compartments of differing pH
If a patient takes an overdose of a weak acid drug, the
excretion of this drug is faster in alkaline urine
Excretion of a weak base is faster in acidic urine
Other body fluids in which pH differences from blood pH may
cause trapping or reabsorption are the contents of the stomach
(normal pH 1.9–3) and small intestine (pH 7.5–8), breast milk
(pH 6.4–7.6), aqueous humor (pH 6.4–7.5), and vaginal and
prostatic secretions (pH 3.5–7)
Ⅱ . Routes of drug administration
Routes of drug administration
Enteral---Oral
Sublingual
Parenteral----Intravenous (IV),
Intramuscular (IM), Subcutaneous (SC)
Other---Oral inhalation, Nasal inhalation,
Intrathecal /Intraventricular, Topical,
Transdermal, Rectal.
po = per os = oral
iv = intravenous = into the vein
im = intramuscular = into the muscle
sc = subcutaneous = between the skin and muscle
ip = intraperitoneal = within the peritoneal cavity
icv = intracerebroventricular =
directly into the ventricle of the brain
Oral ingestion
Major site: intestine
Most common
Convenient, be easily self-administered
Safest
with a low risk of systemic infections
toxicities and overdose may be overcome by antidotes
Economical
Disadvantages of oral administration
Limited absorption of some drugs
Slower rate of absorption
Food may affect absorption
Patient must be responsive
Drugs may be metabolized before systemic absorption
Oral preparations
--- Enteric-coated preparations
Used for drugs that are poorly absorbed from the GI tract: heparin
unstable in the GI tract: insulin
For treatment of unconscious patients
Under circumstances that require a rapid onset of action
Parenteral---advantages
drug
Bloodstream
drug
The rate and efficiency of absorption
depends on
Expression of P-glycoprotein
Effect of PH on drug absorption
Uncharged drug passes through
membranes easily
Concentrations of a drug at the
absorption site is determined by
the relative concentration of charged
and uncharged form
The ratio between the two forms is
determined by the pH at the site of
absorption and by the pKa of the drug
pKa Effect of PH on drug absorption
the ionization constant
A measure of the strength of the interaction of a compound with
a proton
Lower pKa indicates more acidic drug, higher pKa indicates
more basic drug
A real live, actual clinical question...
Aspirin
Aspirin isis an
an acidic
acidic drug.
drug. In
In the
the stomach
stomach will
will itit exist
exist
mostly
mostly in
in ionized
ionized or
or non-ionized
non-ionized form?
form?
NON-IONIZED
Why?
Why?
How will this affect aspirin absorption?
Lipid Bilayer
Ionized
Ionizedform
form
(charged)
(charged)
A-
Ionized
Ionizedform
form
(uncharged)
(uncharged)
HA HA
Moral of the story...
Basic
Basic drugs
drugs are
are best
best absorbed
absorbed from
from
basic
basic environments
environments
So...
To absorption
To absorption ofof an
an acidic
acidic drug…
drug…
acidify
acidify the
the environment
environment
To absorption
To absorption ofof an
an acidic
acidic drug…
drug…
alkalinize
alkalinize the
the environment...
environment...
Question:
How to deal with patients of diazepam overdose
Blood flow to the absorption site
Blood flow to the intestine is much greater than
to the stomach
Total surface area available for absorption
Determination of bioavailability
Factors that influence bioavailability
Bioequivalence and therapeutic equivalence
What is bioavailability
Bioavailability is the fraction of unchanged drug
that reaches the systemic circulation following
administration by any route
Determining bioavailability is important for
calculating drug dosages for non-intravenous
routes of administration
Determination of bioavailability
Plot plasma concentration of the drug
versus time
Measure the AUC of drug
Calculate the ratio of AUC for oral
administration to AUC for IV injection with
equivalent dose
Factors that influence bioavailability
a. Administration route
b. First-pass elimination
c. Solubility of the drug
d. Chemical and physical instability
e. Nature of the drug formulation
Routes of administration and bioavailability
First pass elimination
• Before drug reaches the systemic circulation, the drug can be
metabolized in the liver or gut wall, or excreted to the bile by the liver
• The amount of drugs that gains access to the systemic circulation is
decreased
• May limit the efficacy of many drugs when taken orally
Site of action
Intestine wall
Portal vein
Stool Metabolism
drug
Bloodstream
cell
drug
For a drug administered IV
The distribution phase: a drug rapidly
dispersed from the circulation and enters
the tissues
The elimination phase: drug in the plasma
is in equilibrium with drug in the tissues
Factors that affect drug distribution
Plasma proteins
1. Albumin: Weak acids
2. alpha-acid glycoprotein: Weak bases
Effective TOXIC
Factors that affect drug distribution
Binding of drugs to tissue proteins
Intracellular 28 L
Relative size of various distribution
volumes within a 70-kg individual
Applications of Vd
Intracellular 28 L
Relative size of various distribution
volumes within a 70-kg individual
Applications of Vd
Plasma concentration
• A constant fraction of drug is First order
Time
Kinetics of metabolism
Zero order kinetics :
• Doses are very large, enzyme is
saturated by a high-drug
Zero order
concentration, the rate of
metabolism remains constant
Plasma concentration
over time First order
Sites of metabolism
Most drugs are biotransformed in the liver
It can occur in renal tissue, lungs, blood
plasma, and intestinal mucosa
Renal elimination
(Urine) Billary elimination
(Stool)
Role of drug metabolism
Genes Environment
Genetic variability
Clazolimine concentration
Consequences of Induction
( µg/g tissue )
phenobarbitone
Increase drug metabolism
Decrease drug plasma concentration
Decrease drug activity if the metabolite is inactive
benzo-pyrene
Increase drug activity if the metabolite is active
Decrease therapeutic drug effects Time ( hr )
In rats
Enzyme inhibitors
How to inhibit the enzyme?
• Competition for the same isozyme
• Inhibition of the activity of the enzyme
• Natural substances, e.g. grapefruit and its juice
Consequences of Inhibition
Increase in the plasma concentration of parent drug
Reduction in metabolite concentration
Exaggerated and prolonged pharmacological effects
Increased likelihood of drug-induced toxicity
An important source of drug interactions that lead to serious
adverse events
More important CYP inhibitors: Erythromycin, ketoconazole, ritonavir
Enzyme inducer/ inhibitors---drug interactions
Routes of excretion
Kidney (most important)
Biliary tract and the feces
Others: expired air, sweat, saliva, tears and breast milk
Renal elimination of a drug
Three processes
Glomerular filtration
Drugs enter the kidney through glomerular capillary plexus
Free drugs flow through the capillary slit into glomerular filtrate
Active tubular secretion
By energy-requiring active transport system in proximal tubule
Low specificity, competition between drugs
Passive tubular reabsorption
Renal elimination of a drug
Three processes
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
• Lipid-soluble, uncharged drug may diffuse out of the nephric
lumen of distal convoluted tubule, back into the systemic
circulation
• Changing pH of the urine, increase the ionized form of the drug
in the lumen, minimize the amount of back-diffusion, and finally
increase the clearance of undesirable drug
•Weak acids can be eliminated by alkalinization of the urine
•Weak bases can be eliminated by acidification of the urine
Ⅶ . Clearance by other routes
Other routes of drug clearance
Via intestine
The feces are primarily involved in elimination of unabsorbed orally ingested
drugs or drugs that are secreted directly into the intestine or in bile
Via the lungs
Lungs are primarily involved in the elimination of anesthetic gases
Via milk in nursing mothers
be relevant as potential source of undesirable side effects to the infant
Via sweat, saliva, tears, hair and skin
only to a small extent
Total body clearance
Feces excretion
Clinical situations resulting in changes in drug half-life
Time
Time Amount
Amount
00sec
sec 66mg
mg
10
10sec
sec 33mg
mg
20
20sec
sec 1.5
1.5mg
mg
30
30sec
sec 0.75
0.75mg
mg
Half-life, T1/2
Time it takes for drug concentrations to decrease by one half
First order elimination: Zero order elimination:
t1/2 =0.693/Ke t1/2 = 0.5 C0/k
`Constant rate of Elimination `Rate of elimination
irrespective of plasma proportional to plasma
concentration concentration.
`t1/2 is constant regardless `t1/2 is dependent on drug
of drug amount amount
Plasma Concentration
Plasma Concentration
Slope
= -Ke/2.303
Time ( h Time ( h
Ⅷ . Design and optimization of dosage
regimen
1. Single dose
Absorption = elimination
iv
10
Plasma aspirin concentration (mg/L)
Cmax
6 orally
4
Tmax
Area under curve (AUC)
0
0 20 40 60 80 100 120 ngh/mL
1-3 h for most of drugs
Time (min)
Section 2
Basic concept of pharmacokinetics
A. Time-concentration curve
Minimum toxic concentration
distribution phase
Safety range
Absorption and
Balance phase
threshold dose
Minimum effective concentration
Elimination phase
Tpeak
Duration Time
Latent period Residual period
2. Multiple dose
Constant repeated administration of drugs
To produce a Css > MEC and < MTC
4-5 half-life, 90% of steady-state concentration is
reached in 3.3 half-lives
3.3
Loading dose
Utilized when a therapeutic level is desired quickly
and an initial larger dose is administered followed by
substantially smaller maintenance doses (may
increase risk of toxicity and adverse effects).
Log Concentration
Time Time
4. Bioavailability
Absolute Bioavailability
The fraction of the dose of a drug
(F) that enters the general
circulatory system,
F = (AUCev x Div)/(AUCiv x Dev)
ev: extravascular
Relative Bioavailability
Compurgation of two different drugs or different dosage
forms of same drug
F = (AUCtest x Dstand)/(AUCstand x Dtest)
Relative Bioavailability
Oral administration of digoxin 0.5mg
Pharmaceutical Co. A
Pharmaceutical Co. B
2) Bioavailability
Minimumeffective
Minimum toxic concentration
concentration
Formulation C
Time
Pharmacokinetics
How
Howthe
thedrug
drug
comes
comesand
andgoes.
goes.
Pharmacokinetic Processes
“LADME” is key
Liberation
Liberation Metabolism
Metabolism
Absorption
Absorption Excretion
Excretion
Distribution
Distribution
Liberation
Ex:
Ex:Enteric
Entericcoated
coated
aspirin
aspirinslows
slowsabsorption
absorptioninin
stomach
stomachvs vsnon-coated
non-coated
Absorption
Patient
Formulation
factors
factors
Tablet
Absorbing
disintegration
surface
Blood
Inert ingredient
flow / solvent effects
Solubility
Environmental pH
Disease
Drug pHstates
Interactions
Concentrationwith food, other drugs
Membranes and Absorption
Lipid Bilayer
Hydrophilic
Hydrophilic
Heads
Heads Hydrophobic
Hydrophobic
Tails
Tails
Small, H2O, urea, CO2,
uncharged Swoosh!
O2, N2
a.k.a.
a.k.a.Mass
MassAction
Action
AAreaction
reactionatatequilibrium
equilibrium
responds
respondstotostress
stressininaa
way
waytotobest
bestreturn
returntoto
equilibrium
equilibrium
System
System
atat
Equilibrium
Equilibrium
Intravenous
Fastest, Most dangerous
Endotracheal
Lidocaine, atropine, narcan, epinephrine
Inhalation
Bronchodilators via nebulizers
Transmucosal
Rectal or sublingual
Administration Routes
Intramuscular
Depends on perfusion quality
Subcutaneous
Depends on perfusion quality
Oral
Slow, unpredictable
Little prehospital use
Ionization
Acids
Acids Release/Donate
Release/DonateHH+
+
Ionized
Ionized
HA H+ + A- form
form
Bases
Bases Bind/Accept
Bind/AcceptHH+
+
H+ + B- HB
Non-
Non-
ionized
ionized
form
form
Environmental pH and Ionization
IfIfwe
weputputan
anacidic
acidicdrug
drugininan
anenvironment
environmentwith
withaalot
lotof
ofHH + (low
+
(lowpH)
pH)what
what
will
willthis
thisequilibrium
equilibriumdo?
do?
HA H+ + A-
HA
HA
HA
HA
System
H +
+from
Non-ionized
System
H atatacid
from
Non-ionized Equilibrium
form
acidenvironment
formpredominates!
Equilibrium
environment
predominates!
Distribution
Rate of perfusion
Plasma protein (albumin) binding
Accumulation in tissues
Ability to cross membranes
Blood-brain barrier
Placental barrier
Plasma Protein Binding
warfarin
warfarin(Coumadin)
(Coumadin)isishighly
highlyprotein
proteinbound
bound(99%).
(99%).Aspirin
Aspirinbinds
bindstotothe
the
same
samesite
siteon
onserum
serumproteins
proteinsas
asdoes
doesCoumadin.
Coumadin.IfIfaapatient
patienton
onCoumadin
Coumadinalso also
takes
takesaspirin,
aspirin,what
whatwill
willhappen?
happen?
The
Theblood
bloodbrain
brainbarrier
barrierconsists
consistsof
ofcell
celltightly
tightlypacked
packedaround
aroundthe
the
capillaries
capillariesof
ofthe
theCNS.
CNS.What
Whatcharacteristics
characteristicsmust
mustaadrug
drugpossess
possesstoto
easily
easilycross
crossthis
thisbarrier?
barrier?
Two effects
Transformation to less active metabolite
Enhancement of solubility
Liver = primary site
Liver disease
Slows metabolism
Prolongs effects
Hepatic ‘First-Pass’ Metabolism
Partial reabsorption
Hemodialysis
Renal disease
Slows excretion
Prolongs effects
Active Tubular Transport
Probenecid
Probenecidisismoved
movedinto
intothe
theurine
urineby
bythe
thesame
sametransport
transportpump
pumpthat
thatmoves
moves
many
manyantibiotics.
antibiotics.Why
Whyisisprobenecid
probenecidsometimes
sometimesgiven
givenas
asan
anadjunct
adjuncttoto
antibiotic
antibiotictherapy?
therapy?
AApatient
patienthas
hasoverdosed
overdosedononphenobartital.
phenobartital.Phenobarbital
Phenobarbitalisisan
anacid.
acid.IfIfwe
we
‘alkalinalize’
‘alkalinalize’the
theurine
urineby
bygiving
givingbicarbonate
bicarbonatewhat
whatwill
willhappen
happentotothethe
phenobarbital
phenobarbitalmolecules
moleculesasasthey
theyare
arefiltered
filteredthrough
throughthe
therenal
renaltubules?
tubules?
Non-ionized Ionized
HA H+ + A-
Decreased
Decreasedreabsorption
reabsorption
Increased
Increasedelimination
elimination
Drug Actions – Drug Interactions
Drug actions
How drugs produce changes within the body
Drug effect
Changes that take place in the body as a result of drug action
Slowing down or speeding up processes
Destroying certain cells or parts of cells
Replacing substances that the body lacks or fails to produce
Drug Actions – Drug Interactions
Desired effect
Effect of drug in the body that was intended
Side effect
Additional effect on the body by the drug that was not part of the goal for that medication
Not usually severe enough to warrant discontinuing the medication
Drug Actions – Drug Interactions
Adverse reaction
One in which the body reacts to a drug in an unexpected way that may endanger a
patient’s health and safety
Contraindication
Any special symptom or circumstance that indicates that the use of a particular drug or
procedure is dangerous, not advised, or has not been proven safe for administration
Drug Actions – Drug Interactions
Local effect
Response to a medication that is confined to a specific part of the body
Systemic effect
Generalized or widespread response to a drug by the body because it is absorbed into the
bloodstream
Drug Actions – Drug Interactions
Cumulation
Occurs when a drug is not completely excreted from the body before another dose is
given
Drug starts to accumulate in the body tissues when repeated doses are given
Toxic effects may occur
Drug Actions – Drug Interactions
Idiosyncracy
An unusual, inappropriate response to a drug or to the usual effective dose of a drug
Anaphylactic Shock = severe idiosyncratic reaction
Acute respiratory distress, hypotension, edema, tachycardia, cool pale skin, cyanosis, and
possible convulsions shortly after administration of the medication
Drug Actions – Drug Interactions
Potentiation
Occurs when two drugs administered together produce a more powerful response than the
sum of their individual effects
Tolerance
Resistance to effect of a drug
A characteristic of drug addiction
Pharmacokinetics: Absorption
The rate at which a drug leaves its site of administration, and the extent to
which absorption occurs.
Bioavailability
Bioequivalent
Pharmacology
Routes of medications:
PO (by mouth)
IV (intravenous)
IM (intramuscularly)
SQ (subcutaneous)
SL (sub-lingual)
IO (intraosseous)
Inhalation
Pharmacology
Forms
Solution
Topical
Tablet
Capsule
Suspension
Transdermal
Inhalation
Pharmacokinetics: Absorption
Factors That Affect Absorption
Routes
A drug’s route of administration affects the rate
and extent of absorption of that drug.
Enteral
Parenteral
Topical
Pharmacokinetics: Absorption
Enteral Route
Drug is absorbed into the systemic circulation
through the oral or gastric mucosa, the small intestine, or
rectum.
Oral
Sublingual
Buccal
Rectal
First-Pass Effect
First-Pass Effect
First-Pass Effect
Parenteral Route
Intravenous*
Intramuscular
Subcutaneous
Intradermal
Intrathecal
Intraarticular
*Fastest delivery into the blood circulation
Pharmacokinetics: Absorption
Topical Route
Skin (including transdermal patches)
Eyes
Ears
Nose
Lungs (inhalation)
Vagina
Pharmacokinetics: Distribution
The transport of a drug in the body by the bloodstream to its site of action.
Protein-binding
Water soluble vs. fat soluble
Blood-brain barrier
Areas of rapid distribution: heart, liver,
kidneys, brain
Areas of slow distribution: muscle, skin, fat
Pharmacokinetics: Metabolism
(also known as Biotransformation)
Half-Life
The time it takes for one half of the original amount
of a drug in the body to be removed.
A measure of the rate at which drugs are removed from the body.
Routes of Administration
Oral
Given by mouth and swallowed
Advantage
Easiest and safest method
Most economical method
Disadvantage
Slow method of absorption
Possibility of being destroyed by gastric juices
Routes of Administration
Sublingual
Placed under the tongue – dissolves in saliva
Advantage
More rapid absorption rate than oral
Higher concentration of medication reaches bloodstream
Disadvantage
Not convenient route of administration for bad-tasting medications or irritating medications
Routes of Administration
Buccal
Placed in mouth next to cheek (tablet form)
Advantage
More rapid absorption rate than oral
Higher concentration of medication reaches bloodstream
Disadvantage
Possibility of swallowing the pill
Routes of Administration
Inhalation
Medication is sprayed or inhaled into nose, throat, and lungs
Advantage
Good absorption due to large surface contact area
Provides rapid treatment
Disadvantage
Sometimes difficult to regulate dose
Not suitable method for medications that irritate mucous membrane lining
Routes of Administration
Rectal
Medication inserted into rectum and is slowly absorbed into mucous membrane lining of
rectum (suppository)
Advantage
One method of choice when patient is nauseated or cannot take medications orally
Disadvantage
Absorption is slow and irregular
Routes of Administration
Vaginal
Medication is inserted into the vagina in the form of a suppository, cream, foam, or tablet
Advantage
Easiest method for treating the specific area
Disadvantage
Medications sometimes stain underwear
No other disadvantages
Routes of Administration
Topical
Medication is applied directly to the skin or mucous membrane for a local effect to area
Advantage
Easy method, convenient
Disadvantage
Slow absorption through skin
Routes of Administration
Transdermal
Method of applying a pre-measured amount of medicine to unbroken skin through an
adhesive-backed disk
Advantage
Good method for administering medications slowly into bloodstream over a period of time
Disadvantage
Units can be dangerous if they come in contact with skin of children or pets
Routes of Administration
Parenteral
Administered by injecting medication into body using a needle and syringe
Must be in liquid form
Administered by one of following methods
Intradermal
Intramuscular
Intravenous
Subcutaneous
Routes of Administration
Intradermal
Small amount of medication is injected just beneath epidermis
Used for allergy testing, tuberculin skin testing, and some vaccinations
Needle Angle: 10 to 15-degree
Routes of Administration
Intramuscular
Medication is injected directly into muscle
Used for administering antibiotics, medications that might be irritating to layers of the
skin, and medications that require dosages larger than amount allowed for subcutaneous
injections
Needle Angle: 90-degree
Routes of Administration
Intravenous
Medication is injected directly into the vein, entering the bloodstream immediately
Used when medication is needed quickly
Used for infusing medication over a period of time, by adding the medication to a bag of
intravenous fluids
Needle Angle: 25-degree
Routes of Administration
Subcutaneous
Medication is injected into subcutaneous layer, or fatty tissue of skin
Used for administering insulin, hormones, and local anesthetics
Needle Angle: 45-degree
Parenteral
Routes of Administration
Section 1
Drug Transport
Ch. 2
Absorption
drug transport
distribution
excretion through membranes
metabolism biotransformation
一、 Drug transport across membranes
Cell membrane
1) GI epithelial cells
2) vascular endothelium
3) blood brain barrier (BBB)
4) subcellular membranes
Transfer of drugs across Membranes
Extracellular
Carrier-mediated
Simple diffusion transport
Filtration
(Aqueous diffusion) (Lipid diffusion) 1. Active transport
2. Facilitated diffusion
Intracellular
1 . Simple diffusion
Diffusion through lipid bi-layer
Passive process, concentration gradient
dependent, requires no energy
Molecules move from area of high
to low concentration
Rate of diffusion is proportional to:
1. lipid solubility, the greater the lipid solubility
the faster the rate of diffusion
2. pKa of molecules
3. Concentration difference between both sides
Acidic drug: HA H+ + A (ionized)
Basic drug: BH+ H+ + B (unionized)
Ion trapping
Cell membranes are less permeable to
ionized compounds
H+ H+
A- B BH+
HA
HA A- B BH+
H+ H+
Ionization depends on pH and pKa
[ H+ ] [ A ]
Acidic Ka =
[HA]
drug :
[ A ]
pKa = pH - log
[HA]
[ A ]
10 pH-pKa =
[HA]
Basic drug :pKa-pH
Example
Cromolyn Sodium ( 色甘酸钠 ) pKa=2, Acidic
Stomach : Plasma :
pH=4 pH=7
Total HAH+ + A A + H+HA Total
101 1 102 105 1 100001
[ A ] [ A ]
10pH-pKa = 10pH-pKa =
[HA] [HA]
= 104-2 = 107-2
= 102 = 105
2. Filtration
Water solubility
Small molecular
─ Diameter of aqueous channels in
Capillary wall: 4-8Å ( =1010m )
─ Only for water, urea filtration
Intracellular
cleft
3. Carrier-mediated transport
1. Requiring carrier
2. Structure specific
3. Saturable (functional protein
molecules are limited)
4. Competitive inhibition
Active transport
Against concentration gradient
Facilitated diffusion
Along concentration gradient
Requires no energy