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PHARMACOKINETICS 2) Potency, Affinity and Dose

Part I 3) Number of receptors


Andrew D.inBeavis,
the tissue
Ph.D.
January 11/12, 2018
4) Genetic and environmental variability
Principles of Pharmacokinetics
5) TIME AFTER ADMINISTRATION
• Andrew
What factors determine theD.response
Beavis, to
Ph.D.
a drug? Pharmacokinetics
- 1) Efficacy January 11/12, 2018 “What the body does to the drug”
- 2) Potency, Affinity and Dose
- 3) Number of receptors in the tissue PHARMACOKINETICS
- 4) Genetic and environmental variability
- 5) Time after administration Absorption
o Pharmacokinetics “What the body does to the drug”
Storage

Pharmacokinetics PHARMACOKINETICS Bound


• Diagram representsPHARMACOKINETICS
scope of pharmacokinetics Sites of drug action

• There are barriers in our body to keep things in and out. • Most drugs must be absorbed
Free into the body to
• Water soluble vs lipidAbsorption
soluble drugs…some drugs need both properties reach their site of action
• Barrier drug has to cross to get into tissue (lipid membranes) • Absorption is the process by which
Biotransformation the drug
Excretion
Storage
• Most drugs must be absorbed into the body to reach their site of action gets from the site of administration
• Absorption is the process into the blood stream
by which the drug gets from the site of administration
Bound
• into the blood stream Sites of drug action – For drugs given IV, absorption is bypassed
- For drugs given IV, absorption
Free is bypassed • Absorption is followed by:
• Absorption is followed by:
 – distribution to the tissues, sites of drug action
- distribution to the tissues, sites of drug action – possible PHARMACOKINETICS
biotransformation
- possible biotransformation Excretion
Biotransformation
of a DRUG
– and finally,
Depend elimination
on its from the body,
Physicochemical Properties
- and finally, elimination from the body,
 e.g., in the urine, feces, sweat, and/or exhaled air
o e.g., in the urine, feces, sweat, and/or exhaled air • Most drugs need to cross lipid bilayer membranes
to get absorbed into the body and to enter cells
PHARMACOKINETICS of a DRUG Depend on its Physicochemical Properties – Most drugs are not natural metabolites,
therefore, specific carriers do not exist
• Most drugs need to cross lipid bilayer membranes to get absorbed into the body and to enter
– Hence: mostcells
drugs must be soluble in lipids and fats
- Most drugs are not natural metabolites, therefore, specific carriers do not exist • To access the bilayer which is bathed in aqueous
- Hence: most drugs must be soluble in lipids and fats media, most drugs must also be soluble in water
• PHARMACOKINETICS
To access the bilayer which is bathed inof a DRUG
aqueous media, most drugs must also be soluble
Ideally
PARTITION in water
a drug should have significant solubility in
COEFFICIENT
• Depend
Ideally a drug on its Physicochemical
should Properties
have significant solubility in both fat and water, i.e. it should
both have
fat andawater,
“favorable” partition
i.e. it should have a
coefficient “favorable” partition coefficient
• Most drugs need to cross lipid bilayer membranes
to get absorbed into the body and to enter cells
Partition Coefficient Oil
– Most drugs are=not natural /metabolites, Shake 1
• Partition Coefficient [Drug]oil [Drug]water
to mix
• Favorabletherefore,
if it canspecific
mix withcarriers
bothdooil
notand
existwater
Wait
– Hence: most drugs must be soluble in lipids and fats
Physicochemical
• To access Properties
the bilayerofwhich
Drugsis bathed in aqueous Water
• Most important property is partition coefficient
media, most drugs must also be soluble in water Chemically most drugs may be classified as
• 1) Neutral
Ideallyuncharged drugs

a drug should have significant solubility in
• 2) Weakbothacids
fat and
and weak
water,bases
i.e. itand theirhave
should saltsa
• Partition Coefficient = [Drug]oil/[Drug]water
• 3) Salts“favorable”
of strong acids and strong
partition bases
coefficient
• How is the pc affected by class? Does the class define the pc?

1) NEUTRAL UNCHARGED DRUGS


1
• Neutral uncharged drugs

- Partition coefficient depends on relative numbers of carbons and hydrophilic groups such as -OH
- Ethanol (one OH group and two CH groups) Nice and soluble in water
- Lots of CH groups = don’t like to interact w/ water = not soluble.
- Ethanol is freely soluble in water and lipids and has a very good partition coefficient (PC)
- Sorbitol with many OH groups (one per C) is very hydrophilic, poorly lipid soluble and therefore has a poor (very
low) PC
- Steroid drugs/hormones such as dexamethasone and testosterone have very few hydrophilic OH groups per C and are
lipophilic and insoluble in water and have a poor (very high) PC
2 3
and

• A base (B) is a compound that can accept a


methasone
proton from an acid such as water
philic OH Pharmacokinetics I 1/5/2018
soluble in 2) Acids and Bases B + H2O BH+Pharmacokinetics
+ OH- I 1/5/2018
• An acid (HA) is a compound that can donate a proton to a base such as water
HA + H2O A- + H3O+
• A base (B) is a compound that can accept a proton from an acid such as water
B + H2O BH+ + OH-
• WEAK ACIDS and WEAK BASES
- A Equilibria
Acid/Base weak acid (HA) or a weak base (B) is a compound/drug that canEquilibria
Acid/Base donate or accept a proton reversibly
HA + H2O A- + H3O+
Acid/Base Equilibria Acid/Base Equilibria
B + H2O BH+ + OH- • Why are many drugs weak acids or weak
ASES • The term “weak”WEAK indicatesACIDS
that bothandtheWEAK
ionized BASES
and un-ionized
bases? forms
• Why areofmany
the drug areweak
drugs present in equilibrium
acids or weak in the
Acid aqueous + H+
Basesolution
+ Pharmacokinetics I bases? 1/5/2018
B)relationship
is a • between the Acid Baseof+: H
Pharmacokinetics
• Simplification
concentrations
Simplification I • The charged and uncharged species1/5/2018 have
• The isrelationship - + Hdifferent
• The charged and
physico-chemical properties: uncharged species have
wo drug
cept a species defined bybetween
the the concentrations
HA + H2O Aof 3O
+
the two different physico-chemical properties:
librium constant (Kdrug
a):
species is defined by the – Different water and fat solubilities
equilibrium constant (KAcid – Different water and fat solubilities
Base Acid Different partition coefficients
a): Base
K a = [Base]•[H +]/[Acid]
– Charged species usuallyDifferent
more waterpartition coefficients
soluble
+
• ignoring K the =water, the
[Base]•[H
ignoring reaction
+]/[Acid]can be written
the water, the reaction can be written – Charged
a – Neutral species usually morespecies usually more water soluble
lipid soluble
H- Acid/Base Equilibria HA ßà
Acid/Base Equilibria HA A- + H+ A- + H+ Acid/Base Equilibria Acid/Base
– Neutral speciesEquilibria
usually more lipid soluble
ortant consequence:
• or • Consequence is the drug can be transported by
• Important
[base]/[acid] ratio is consequence:
dependent or on the pH multiple •andWhy
•are
Consequence
different
manymechanisms
drugs
is the drug can be transported by
weak acids or weak
he ionized Acid ßà Base + •H+ Why are many drugs weak acids or weak
The [base]/[acid] ratio is dependent Acid on the Base pH + H +
bases? multiple and different mechanisms
present in Acid
• The latter
Base relationship
Acid
+ H+ Baseis+true
H+ whether or not the uncharged
bases? drug species is an acid or a base
• The latter relationship is true whether or not the • The charged and uncharged species have
• The
The relationship relationship
between between the of
the concentrations
uncharged drug
concentrations of • The charged and uncharged species have
species is an acid or a base
• theAcid/Base
two Equilibria different physico-chemical
different physico-chemical properties: properties:
he two drug species is drug species
defined by theis defined by the
equilibrium constant (K Acid
): ßà Base + H+ – Different water – Different
and fat water and fat solubilities
solubilities
equilibrium constant (Ka): a
Different partition coefficients
• Different
The relationship between the concentrations of the two partition coefficients
drug species is defined by the equilibrium constant (Ka):
K +
Ka = [Base]•[H
2 a = [Base]•[H ]/[Acid]
+]/[Acid]
– Charged species –usually
Charged species
more waterusually
soluble more water soluble
Ka = [Base]•[H+]/[Acid]
CIDIC FUNCTIONAL

GROUPS -1 
The [base]/[acid]–ratio
Important consequence: ACIDIC
Neutral
isspecies
–FUNCTIONAL
Neutral
usually
dependent more
on pHsolubleGROUPS -2
species
lipid
the
usually more lipid soluble
• ACIDIC
Important
mportant consequence: FUNCTIONAL
consequence: GROUPS -1 • ACIDIC
Consequence is the FUNCTIONAL
drug
• Consequence is the drug can be transported can
bybe transportedGROUPS
by -2
boxylic
The acidsTheratio
[base]/[acid] [base]/[acid] ratio
onisthe
dependent on the pH Amides
multiple and are
multiple
different not
and acids
mechanisms or bases,
different but
mechanisms
• Why isare
dependent
many drugs
• Carboxylic acids
pH acids
weak or weak bases? Amides are not acids or bases, but
- The charged and+uncharged
H+ species have•different
Imides physico-chemical properties:
o Different water and fat solubilities + Hà+
Different partition coefficients
• Imides
ols are not usually acidic, e.g.
o Charged species
C2H5OH , but more water soluble – Neutral species usually more lipid soluble
usually + H+
nols Alcohols are not usually
- Consequence is theacidic, e.g.beC2transported
drug can H5OH, but by multiple and different mechanisms
+ H+
• Phenols
+ H+
• ACIDIC
ACIDIC FUNCTIONAL FUNCTIONAL
GROUPS
Acidic Functional -1 GROUPS -1 + ACIDIC
Groups + H
ACIDIC FUNCTIONAL
FUNCTIONAL
• Ureides GROUPS -2 GROUPS -2
ls • Ureides
Carboxylic acids Amides are not acids or bases,
Amides are notbut
acids or bases, but
•• Carboxylic
Enols acids
+ H+
+ +
++HH + H+ • Imides + H+
• Imides
+ H+
cohols are not usuallyare
Alcohols acidic, e.g. C2H5acidic,
not usually OH, bute.g. C2H5OH, but
+ H+ + H+
Phenols • Phenols
+ H+ + H+ • Ureides • Ureides
Enols • Enols
+ H+ + H+
+ H+
CIDIC FUNCTIONAL GROUPS -3 + H+ BASIC FUNCTIONAL GROUPS
ACIDIC FUNCTIONAL GROUPS -3 BASIC FUNCTIONAL GROUPS
• Primary amines
fonamides • Primary amines + H+
• Sulfonamides + H+
+ H+ • Secondary amines
+ H+ • Secondary amines
+ H+
ACIDIC FUNCTIONAL
fonylureas GROUPS -3 GROUPS -3 BASIC FUNCTIONAL GROUPS
BASIC FUNCTIONAL GROUPS
ACIDIC FUNCTIONAL + H+
• Sulfonylureas • Tertiary
• Primary amines
amines
Sulfonamides• Sulfonamides • Primary amines amines
• Tertiary + H+ + H+
+ H+
+ H+
+ H +
+ H+
• Guanidines
+ H+ + H•+ Secondary amines
• Secondary amines
• Guanidines + H+ + H+ + H+
Sulfonylureas
• Sulfonylureas • Tertiary amines
+ H+
important to treat diabetes • Tertiary amines
+ H+
+ H+
+ H+
+ H+ • Guanidines
3 • Guanidines
3 + H+
+ H+
Henderson-Hasselbalch
Henderson-Hasselbalch Equation
Equation Salicylic Acid: Typical weak acid drug
Should know this
Pharmacokinetics I 1/5/2018
Pharmacokinetics I 1/5/2018
pKa = 3
Needs knowledge
of logarithms Ka = 10-3
Pharmacokine
Need to know
Lipid-soluble Water-soluble
pH -log[H+] Acid Base
macokinetics II Henderson-Hasselbalch Equation 1/5/2018 Salicylic
pKa Acid:
-logKTypical
a weak acid drug
rmacokinetics 1/5/2018
Henderson-Hasselbalch Equation
Henderson-Hasselbalch Salicylic Acid: Typical weak acid drug
Equation – almost!
Should know this • Ka = [Base].[H3O+]/[Acid] = 10-3
Should know this or Ka = {[Base]/[Acid]}.[H = 3+] = (B/A) x 10-7
pKa3O
Pharmacokinetics I Antilog of difference knowledge1/5/2018
between
Needs Henderson-Hasselbalch Equation
pH and pK gives [B]/[A] pKa = 3
• For salicylate at pH 7, [Base]:[Acid] = 10,000:1
of logarithms
Needs knowledge K = 10-3 a


of logarithms
Amount of neutral charged species is dependent on pH Ka = 10-3 Should know this
Need to know
Salicylic
SalicylicAcid:
Acid:Typical
Typicalweak
weakacid
acid drug
drug +] Lipid-soluble Water-soluble
pH Need
-log[H
to know Acid Base
Needs knowledge
Salicylic Acid: Typical weak acid drug (Aspirin)
pH -log[H+]
Lipid-soluble pKa -logKa Water-soluble of logarithms
Acid pK -logK Base
Henderson-Hasselbalch a a
Need to know
Salicylic Acid: pK
pKTypical
a ==33
a weak
Equationacid drug
– almost!
Henderson-Hasselbalch • Ka = [Base].[H3O+]/[Acid] = 10-3 pH -log[H+]
Equation – almost! •or K K = = [Base].[H O+]/[Acid]
{[Base]/[Acid]}.[H O +]==10-3
(B/A) x 10 -7
Diphenhydramine: Typical KKa ==10 weak
-3 base drug
Antilog of difference between
10-3 3) STRONG ACIDS and BASES
a a 3 3
+ x 10-7
• Fororsalicylate
Ka = {[Base]/[Acid]}.[H 3O ] = (B/A)
a
pH and of
Antilog pKdifference
gives [B]/[A]
between at pH 7, [Base]:[Acid] =Henderson-Hasselbalch
10,000:1
Benadryl® Equation – almost!
Lipid-soluble
Lipid-soluble
pKa = 3 pH and pK gives [B]/[A]
Water-soluble
Water-soluble
• A salt of asalicylate
• For strong acid or base
at pH is always = 10,000:1
7, [Base]:[Acid]
dge
ms Acid
Acid pK
pKa = 9
pKa -logK
-logKK
Base
Base dissociated in aqueous solution Antilog of difference between
a a = 10-3 aa
– The drug molecules are always charged pH and pK gives [B]/[A]
Ka = 10-9
w ++ • Anions of strong acids
+] •• KLipid-soluble
Kaa==[Base].[H
[Base].[H3O 10-3-3
]/[Acid] =Water-soluble
3O ]/[Acid] = 10
or Acid + Base x 10-7-7
orKKaa==Base
• Lipid-soluble
{[Base]/[Acid]}.[H
pKa -logKa3O
{[Base]/[Acid]}.[H +] =Water-soluble
(B/A)
3O ] = (B/A) x 10
– R-OSO3-, R-OPO3-
For salicylate pK
at pH -logK[Base]:[Acid] Acid • Cations of3)strong bases ACIDS and BASES
ch • •• For
Forsalicylate
salicylateat
Diphenhydramine: pH7,7,
atapH [Base]:[Acid]
7,Typical
a
weak=base
[Base]:[Acid] =10,000:1
= 10,000:1
drug
10,000:1 STRONG
•Diphenhydramine:
K3aO=+]/[Acid]
[Base].[H +]/[Acid] = 10-3
• Ka = [Base].[H = 103-9OTypical weak base drug – Quaternary3)ammonium
STRONG group (R4-N+)and
ACIDS BASES
Diphenhydramine:
or Ka =or KBenadryl® Typical
3O ] =weak
a = {[Base]/[Acid]}.[H
{[Base]/[Acid]}.[H + base
O +] =xdrug
10-9 =3(B/A) 10-7 (Benadryl)
(B/A) x 10-7 • Drugs
• A with multiple
salt of a strongweak
acidacids or is
or base basic groups,
always
een
• Consequently, Benadryl®
for diphenhydramine Diphenhydramine: Typical weak base drug
] • For salicylate a = 9 at pH 7,= 10,000:1
at pH 7,pK[Base]:[Acid] behave Alike
salt strong
•dissociated acids/bases,
of ainstrong acid or because
base
aqueous solution is the
always
[Base]:[Acid] =1:100, i.e. (B/A) pKa== 109 -2 concentration
The drugofmolecules
– dissociated uncharged are species
in Benadryl®
aqueous is negligible
solution
always charged
Ka = 10-9

Ka = 10-9 – The of
• Anions drug molecules
strong acidsare alwayspKcharged
a = 9

Water-soluble •– Anions
R-OSO3 , R-OPO3- acids
of
- strong
3)
3)STRONG
STRONG
Lipid-soluble Base ACIDS
ACIDSandandBASES
BASES -9 Ka = 10
pKa -logKa Acid
Water-soluble – R-OSO
• Cations
-
, R-OPO
of 3strong bases
3
-
Lipid-soluble Base
pKa -logKa Acid •– Cations of strong bases
••• K
AA saltof
salt ofaastrong
strong
+ acidororbase
acid
a = [Base].[H3O ]/[Acid] = 10
-9baseis isalways
always Quaternary ammonium group (R4-N+)
Lipid-soluble Base Water-soluble
g dissociated
dissociated
or K = in
in aqueous
aqueous solution
+]/[Acid]solution
{[Base]/[Acid]}.[H O +-9
] = 10 -9 = (B/A) x 10-7
• Drugs– Quaternary
with multipleammoniumweak pK
group
acids-logK
(Ror+
4-N )
abasic groups,Acid
• • K a = a 3) STRONG
[Base].[H 3 O ACIDS
=3 10 and BASES a
or drug
––The
The Kdrug
• • Consequently, a = {[Base]/[Acid]}.[H
for diphenhydramine
molecules
molecules diphenhydramine
Ipratropium: a Quaternary Ammonium Drug
arealways
are always
+ = 10-9 = (B/A) x 10-7
3O ]charged
charged at
at pH
pH 7,7, [Base]:[Acid] =1:100, Heparin:
•behave
Drugs
i.e. (B/A)
• K with
like Strongly
=strong-2
multiple acidic
+ weak
10 acids/bases,
a = [Base].[H3O ]/[Acid] = 10
drug
acids or basicthe
-9because groups,
• Consequently,
[Base]:[Acid]
• A salt
•• Anions
Anions ofofof for
=1:100,
a strong
strong
strong acids
acids diphenhydramine
i.e.or(B/A)
acid base =is 10alwaysat
-2 pH 7, behave like aof
concentration or K strong
= acids/bases,
uncharged species
{[Base]/[Acid]}.[H 3 O because the
is negligible
+] = 10-9 = (B/A) x 10-7

[Base]:[Acid] =1:100, i.e. (B/A) = 10 -2


3) Strong – Acids
dissociated
R-OSO - and
-, R-OPO
– R-OSO3 3, R-OPO3 3 in Bases
aqueous
- - solution concentration
• of
Consequently, uncharged
for species
diphenhydramine is negligible
at pH 7,
• A salt – of adrug
The strong acid orarebase
molecules alwaysis always
charged dissociated in aqueous solution [Base]:[Acid] =1:100, i.e. (B/A) = 10-2
•• Cations
- •The
Cationsof ofstrong
drug of
strongbases
molecules
bases
are always charged
– Anions
Quaternary
– Quaternary strong
ammonium
ammonium acidsgroup(R
group (R4-N ++
4-N) )
• Anions of strong acids
-, R-OPO -
– R-OSO
le
-•• Drugs
Drugs
R-OSO with
with - 3multipleweak
3 , multiple
R-OPO 3
-3weakacidsacidsororbasic
basicgroups,
groups,
Ipratropium

behave(Atrovent®),
Cationslike of strong
strong bases
acids/bases, pKa = 9.7 the
Atropine,because
behaveammonium
Cations
a• quaternary like
of strongstrong bases acids/bases,
a tertiarybecause
ammonium the
concentration
– Quaternary
concentration
Quaternary
• Ipratropium:
compound aofof
ammonium uncharged
ammonium
uncharged
Quaternary group species
group
species
Ammonium
compound isis+negligible
(R(R4-N+)
4-N ) negligible
Drug Heparin: Strongly acidic drug
• Ipratropium:
Drugs
• Drugswithwith multiplea Quaternary
multiple weak weakacids Ammonium
acidsor basic
or basic Drug
groups, behave like• strong
groups, Heparin:
acids/bases,
Many charged groups Strongly
because
and very acidic drug of
thepKconcentration
low a of sulfuric acid
• Foruncharged behaveatspecies
atropine pH7,
like is negligible
[Base]:[Acid]
strong acids/bases, = 1:500because the make it Ipratropium:
impossible to form ana Quaternary
uncharged structureAmmonium Drug
• Ipratropium concentration
always carries of uncharged species is negligible
a + charge, • Even without a charge, sugar molecules have a very
Ipratropium: + a Quaternary Ammonium Drug low partition coefficient
it has no H that can be removed
• For atropine at pH7, [Base]:[Acid] = 1:500
• Ipratropium always carries a + charge, it has no H+ that can be removed
Ipratropium Heparin:
(Atrovent®),
Heparin: Strongly
Strongly acidic
right acidic
drug
Atropine,
thedrug
pKa = 9.7
• aUsed for
quaternary COPD, goes
Ipratropiumammonium
(Atrovent®),
into
a tertiarylungs
Atropine,
(don’t want it to go thru the gut)
ammonium
pKa = 9.7 4
compound compound Ipratropium (Atrovent®), Atropine, pK = 9.7
a
a quaternary ammonium a tertiary ammonium
a quaternary ammonium a tertiary ammonium
compound compound • Many charged groups
compoundand very low pKa of sulfuric acid
compound
g • For atropineHeparin:
at pH7,Strongly acidic= drug
[Base]:[Acid] 1:500 •make it impossible
Many to form
charged groups andanvery
uncharged
low pKastructure
of sulfuric acid
make it• impossible tosugar
form an uncharged structure
• Ipratropium always carries a + charge, 1:500
• For atropine at pH7, [Base]:[Acid] = • Even without Fora atropine
charge, molecules
at pH7, have
[Base]:[Acid]a very
= 1:500
•it Ipratropium
has no H+ thatalways carries
can be a + charge,
removed •low partition
Even withoutcoefficient
a charge, sugar molecules have a very
• Ipratropium always carries a + charge,
low partition coefficient
it has no H+ that can be removed +
it has no H that can be removed
Tobramycin (Nebcin®)
Ipratropium: a Quaternary Ammonium Drug Heparin: Strongly acidic drug
Heparin: Strongly Acidic Drug
• Many charged groups and very low pKa of sulfuric acid make it
impossible to form an uncharged structure
Pharmacokinetic
• Even without a charge, sugar molecules have a very low partition
coefficient Aminoglycosides:
Ipratropium (Atrovent®), Atropine, pKa = 9.7 Drugs with Multiple
a quaternary ammonium a tertiary ammonium
compound compound
Positive Charges
• Many
• Multiple -NHcharged groups and very lowTobramycin
2 groups make it essentially
pKa of sulfuric acid
(Nebcin®)
• For atropine at pH7, [Base]:[Acid] = 1:500 maketoitform
impossible impossible to formstructure
an uncharged an uncharged structure
Tobramycin (Nebcin) • Even• Even
without without
a a
charge, charge,
sugar sugar molecules have a very
molecules
• Multiple •-NH2
Ipratropium alwaysit carries
groups make a + charge,
essentially impossible to form an uncharged
have a structure
low
very partition
low coefficient
partition coefficient
• it has
Even without no H+ that
a charge, canmolecules
sugar be removedhave a very low partition coefficient

Aminoglycosides:
4 Drugs with Multiple
LIPINKSKI’S “RULE-of-FIVE” (1997) Positive Charges
• Poor ability to cross lipid barriers, e.g. absorption from GI tract, is predicted •ifMultiple
a drug-NH has more
2 groups than
make 1 of following
it essentially
properties: impossible to form an uncharged structure
• Even without a charge, sugar molecules
• 1. Partition coefficient > 105 (logPC > 5)
 have a very low partition coefficient
- “Good” range PC 0.4 – 400,000 (Ghose, et al 1999)
• 2. More than 5 H-bond donors (e.g. N-H, O-H) TRANSPORT of DRUGS
• 3. More than 10 H-bond acceptors (e.g. O, N)
• 4. Molecular weight > 500

Transport of Drugs • Three major transport mechanisms


• Three major transport mechanisms** 1) Diffusion across the lipid bilayer
1) Diffusion across the lipid bilayer 2) Filtration through pores
2) Filtration through pores
TRANSPORT of DRUGS
3) Active or passive transport by specialized
3) Active or passive transport by specialized transport systems transport systems
• Three major transport mechanisms
1) DIFFUSION ACROSS BILAYERS
1) Diffusion across the lipid bilayer
• To diffuse across the bilayer, a drug

2) Filtration through pores
- Must have a “favorable” partition coefficient = what [] of drug in membrane. 3) Active or passive transport by specialized
- Hence, it must be uncharged transport systems
• Important for

- Absorption from GI tract

DIFFUSION of UNCHARGED DRUGS
- Entering cells (if receptor is intracellular)

- Entering CNS (if receptor is inside BBB) Side 1 Side 2
Drug Conc. = C1 Drug Conc. = C2
Lipid
Diffusion of Uncharged Drugs DIFFUSION of UNCHARGED DRUGS
• Hydrophilic head of lipid bilayer interacts with water and
Side 1 Side 2
charged groups. Tails can’t hydrogen bond w/ H2O. Drug Conc. = C1
Lipid
Drug Conc. = C2
• Dots = ethanol, good partition coefficient and can diffuse across
bilayer
• Movement of drugs to side 2. Rate depends on [] of side 1.
• Movement will continue till [] is equal on both sides and rate is Rate of transport = k(C1 - C2)
equal. k will depend on the PC
At Equilibrium: C1 = C2
Rate
and of
Cmtransport
/C1 = PC= k(C1 - C2)
Passive Diffusion k will depend on the PC

Equilibrium: C1 = C2
Definition: Passive transport: Transport of the drug is driven by the concentration gradient of the drugAtacross
and Cm/Cthe
1 = PC
membrane, i.e. it is a spontaneous downhill process that dissipates the gradient. Aka goes from high to low []
5
Passive Diffusion Of Weak Acids And Bases Across Lipid Bilayers 5
• e.g. salicylic acid and diphenhydramine
Pharmacokinetics I 1/5/2018
Transport of a Weak Base
• These drugs exist as two species
 Water Transport of a Weak
PASSIVE
Base of Water
DIFFUSION
PASSIVE DIFFUSION of
- Water soluble, lipid insoluble, charged form (acid) WEAKLipid ACIDS and BASES
10-7 1 WEAK ACIDS and BASES
ACROSS LIPID 1BILAYERS 10
-7
- Potentially lipid soluble, uncharged form (base)
H+ ACROSS LIPID BILAYERSH+
• Ratio is 1 / 100 (due to 10^-9 = base/acid x 10^-7) Transport of a Weak Base
Water Water
• Charged species act as an anchor
PASSIVE

DIFFUSION of
Uncharged doesn’t bind as tightly and can go into 10 •Rate
-7 e.g. of
salicylic acid and diphenhydramine
transport
1
Lipid
1 10-7
WEAKmembrane
ACIDS=and BASES
neutral species/drug and can move to • e.g. salicylic
Hdepends
+ acid and diphenhydramine H+
on conc.
of the base (3p’s)
ACROSS LIPID
other BILAYERS
side, back in water. PASSIVE
It can then DIFFUSION
bind to protonof
Rate of transport
on other side => chargedWEAK species.ACIDS and BASES depends on conc.
• Charged species can’t crossACROSSbecause of lipid
LIPID bilayer
BILAYERS 100 H+ H+ H+
of the base (3p’s) 100
• Tighter it binds = higher PKa
100 H+ H+ H+ 100
e.g. salicylic
- acid andondiphenhydramine
Depends partition coefficient
• Rate of transport = •howe.g.fast species
salicylic acidcan
andcross lipid bilayer • These drugs exist as two species
diphenhydramine
- PKa •Water
– Water soluble, These
lipiddrugs exist ascharged
Transport
insoluble, oftwo species
a Weak Acid(acid)Water
form
- pH – Water
1 soluble, lipid insoluble, charged form (acid)
– Potentially lipid soluble, uncharged form (base)
- Partition coefficient. Water –
HOTransport of a Weak Acid
Potentially lipid soluble, uncharged HOform (base)
1
Water
1 Rate of transport
Transport of a Weak Acid HO depends on conc. HO 1
of the acid (3 p’s)
• These drugs exist as two species
 10 -7 10000
10-7
- Potentially lipid soluble, uncharged form (acid)
 Rate of 10000
transport
+
H depends - O on conc.- O H + -O
- Water soluble, lipid insoluble, charged form (base) of the acid (3 p’s)
• What happens Water Transport of a Weak Acid
if the pH is not the same on each side ofWater the
Lipid
10 -7 10000
10-7 10000
• These drugs exist as two species
Transport of a WeakHOAcid
membrane? 1
Water HO 1 H+ - O – Potentially - lipid
O soluble, uncharged H+ form- (acid)O
- Effect of pH gradients on the equilibrium distribution of weak
1 – Water soluble,What lipid
Lipid happens
insoluble, charged form (base)
acids and bases Rate of transport
• Charged particles takes HOtoodepends
much 1onenergy
conc. to cross barrier and neutral species
• Thesewilldrugsreadily if the
exist crosspH is
as two not the same
species
of the acid (3 p’s)
What
– Potentially
on each
lipidhappens
side of the membrane?
soluble, uncharged form (acid)
10-7 10-7 10000
10000
Rate of transport
Advantage of weak acid & base
O lipid bilayerif and
–the
WaterpH is lipid
soluble, notinsoluble,
the same
charged form (base)
conc. charged,Hmore-water
+ O soluble, H+cross-thru
depends
99% or on more - O can easily become
• Effect charged again. on
of pH gradients “flip-flop”
the equilibrium
of the acid (3 p’s) Lipid on each side of
distribution the
of
Transport membrane?
weak of acids
a Weakand Base
bases
0-7 10-7 10000 Water Water
Transport of a Weak
10000 Base
• These drugs exist as two species 10-2
O • What if the pH is not the
+ same onsoluble,
each uncharged
side?
 form (acid) 10-7 Base
- -O H
– Potentially
- O
lipid
H +
on the equilibrium H
+
• pH 7 on the left and– Water
pH 2 soluble,
on the lipid • Effect of pH gradients
rightinsoluble, charged form (base)
1
- the cation Lipidaccumulates on the side with the lower pH ?
1
distribution
Water
of weakTransport acidsofand a Weak basesBase Water
- weak base will accumulate to the side that is more acidic (low pH)
ese drugs exist as two species 10-2
10-7 Pharmacokinetics I Base
1/5/2018
PotentiallyTransport
lipid soluble,
of auncharged
Weak Acid form (acid) ?7
10
H+ 102 H+ Acid H+ H+
• What if the pH is not the
Water soluble, lipid insoluble, charged formsame(base)
on each side? 1 Lipid
Transport of a Weak Base ?
1
- pH 7 on the left and
Water pH 9 on the right Water Water Transport
• What if the pH is notofthe
a same
WeakonAcid
each side?Water
- the anion accumulates on the side with the higher pH 10-2 – pH1 7 on the left and pH 2 on the right
Acid
Base “ION TRAPPING”
weak acid will10accumulate
-7
- to the side that is more alkalotic. (high pH) HO
– the cation accumulates HOthe lower1
on the Diffusion
Summary: side with ?pH
H+ H+
• The difference in concentrations of weak acids
1 102 H+ Acid H+ ?7
10
“Ion Trapping” ?
1 between blood (pH 7.4) and different
and bases
• To undergo diffusion across lipid bilayer
compartments brought about by a difference in Lipid(nonionic diffusion), a drug must
membranes
• The difference in concentrations of weak acids pH isand bases
frequently between
referred blood
to as “ion-trapping”.
– Have favorable partition coefficient
6
(pH 7.4) and different compartments • Examples: pH • What if the 10-7 pH is not the same on each
– 4Have an uncharged form
10
10-9 side?10 ?6
Transport ofabout
brought a Weak Base
by10a2 difference
H+ in pH is
Water
Stomach
H+
Vaginal
Acid secretions Water
2
? 73.8-4.5
10 Transport
– pH 7Hon of
+ the-left a Weak
O• Examples and Acid pH 2H on+ the right
Water
-O
frequently referred to as “ion-trapping”.Lipid
Prostatic Secretions 7.2-8 – the cation – Neutral drugs
accumulates on the side
Lipid with the lower pH Base
10 -2 Urine 4.5-8 1(5.5-6.5 usual) – Weak acids and bases
Acid
Base • Very important for absorption and distribution,
• What if the pH is not the sameBreast
on milk
each side? 7.2
HO • What if the pH is not the same on and
HOthe CNS each
?cellsside?
1
H+ Summary: Diffusion H+ Jejunum, Ileum 7.5-8.0 especially for entry into
– pH 7 on the left and pH 2 on the right – pH 7 on the left and pH 9 on the right
• To undergo diffusion across lipid bilayer membranes (nonionic diffusion), a drug must 6
1 – the cation accumulates on the side with the lower pH
?
1 coefficient
 – the anion accumulates on the side with the higher pH
- Have favorable partition
- Have an uncharged form
• Examples
 6 TRANSPORT 10THROUGH
-9 PORES
10 ?6
- Neutral drugs
 2) TRANSPORT/FILTRATION 10-7 104 Blood Endothelium Interstitium
- Weak acids andAcid
basesH+ 10?7 THROUGH PORES
H+ H+between-cells
Othat +N +N H
+ -PoresO
allow
in capillaries
transport of most
• Very important for absorption and distribution, especially for entry into the CNS and cells
• Pores are transport pathways drugs into
Base
and out of
Lipid allow all drugs small enough to fit through them Lipid interstitium
to move between aqueous compartments Lipid
hat if the pH is not the same on each side? • What if the pH is not the+Nsame on each side?
• The major driving force for transport is the
+N
hydrostatic pressure gradient
pH 7 on the left and pH 2 on the right • Where are pores found? – pH 7 on the left and pH 9 on the right
– Have favorable partition
pH is frequentlycoefficient
referred to as “ion-trapping”.
• Examples: pH
– Have an uncharged
• Examples:form pH
Stomach 2 Stomach 2
Vaginal secretions 3.8-4.5 • Examples Vaginal secretions 3.8-4.5 •

Prostatic Secretions 7.2-8 – Neutral drugs Prostatic Secretions 7.2-8


Urine 4.5-8 (5.5-6.5 usual)
– Weak acids andBreast
bases
TRANSPORT/FILTRATIONUrine 4.5-8 (5.5-6.5 usual) milk 7.2 •
2) THROUGH PORES Jejunum, Ileum 7.5-8.0
Breast milk 7.2 • Very important for absorption and distribution,
• Pores are transport pathways between cells that allow
Jejunum, Ileum 7.5-8.0all drugs small enough to fit especially
through them to into
for entry movethe between
CNS and cells
aqueous compartments
• The major driving force for transport is the hydrostatic pressure gradient
• Where are pores found?
2) TRANSPORT/FILTRATION
- Most capillaries (blood vessels) THROUGH PORES
- Kidney glomerulus! • Pores are transport pathways between cells that
• Charged/fixed charges can’t cross endothelium and need to go to pore => pathway ofTRANSPORT allow allTHROUGH
least resistance. drugs small enough PORES
to fit through them
to move between aqueous compartments
- Most important mechanism of 2) getting
TRANSPORT/FILTRATION
things out of blood and into the tissues. Blood • The Endothelium Interstitium
major driving force for transport is the
THROUGH PORES hydrostatic pressure gradient
• Where are pores found?
Pores in capillaries
Transport Through Pores • Pores are transport pathways between cells that +N +N– Most capillaries allow transport of most • P
drugs
Most into and out of
important
am
• Pores are essential for distribution of quaternary ammonium drugs,
allow all drugs small enough to fit through them
– Kidney glomerulus
interstitium –

e.g. succinylcholine, etc.
 to move between aqueous compartments Lipid


- Water soluble, charged drug• Thethat
majoris driving
usually lipid
force for insoluble
transport is the
hydrostatic pressure gradient
+N +N
Transport of Heparin?
Transport of Heparin? • Where are pores found?
Blood Interstitium
• Some drugs are too big to “go– Most
withcapillaries
the flow”
 Most important Endothelium Pharmacokine
• Pores are essential for distribution of quaternary • P
– Kidney glomerulus ammonium drugs, e.g. succinylcholine,
- - - - - - - - - - - etc.
Pores in capillaries m
- Heparin is essentially limited to the plasma compartment too small to allow
– Water soluble, charged drug that is usually lipidpassage
insoluble
of Heparin • O
• Pores in capillaries too small to allow passage of Heparin • T
Lipid
e
-----------
Pores Co
i
• Pores are non-selective holes for the passage of molecules from the capillaries to the interstitium • Some drugs are too big to “go with the flow” s
– Heparin is essentially limited to the plasma compartment
• Only the size of the molecule restricts transport Reminder: LOCATION OF PORES
Transport of Heparin? PORES
- pH, pK, PC have no effect for most drugs 7

Blood
This is the most important mechanism for the entry of mostInterstitium
drugs into• mostMost tissues
capillaries
Endothelium • Pores are non-selective holes for the passage of
• *Consequence: the rate of entry of the drug into most Pores
tissues is not
in capillaries
limited by not
– But lipid solubility,
molecules
in the brainfrom
- thebut
the by the blood
capillaries
“blood-brain the flow
tobarrier” interstitium
----------- too small to allow
passage of Heparin • Only
• Passive the size
diffusion of theis molecule
of drugs necessary restricts transport
Reminder: LOCATION OF PORES – pH, pK, PC have no effect for most drugs
• Most capillaries Lipid • Kidney •glomerular capillaries
This is the most important - large
mechanism for the
- But not in the brain - the “blood-brain barrier” specialized pores
entry of most drugs into most tissues
o Passive diffusion of drugs is necessary -----------
Consequence: the rate of entry of the drug
• Kidney glomerular capillaries - large specialized pores • Liver sinusoids have a special endothelium,
into most tissues is not limited by lipid
• Liver sinusoids have a special
• Someendothelium,
drugs are too bigwhich hasthe
to “go with very which
large regulated
flow” has“fenestrae”
pores solubility, butregulated
very large and noblood
by the pores
basement
flow
membrane, so there is no barrier to isproteins
– Heparin such toasthealbumin
essentially limited plasma compartment “fenestrae” and no basement membrane, so
there is no barrier to proteins such as albumin
3) ACTIVE TRANSPORT OF DRUGS
7
• Passive diffusion across a bilayer membrane is a spontaneous downhill process that dissipates the gradient of the
diffusing species
• In contrast, active transport couples the transport to a chemical reaction or the transport of another species using energy
from the cell to drive transport, i.e. it is not spontaneous, and can generate a gradient

Active Transport Water Active Transport Water


• Transported species may have a net charge
 Side 1
Lipid
Side 2
- Charged forms of bases, anions of acids, fixed charge + -
+
- Permanently charged quaternary drugs
• Drugs with same charge can compete with each other + Active
• Transporter uses E to transport to other side regardless of the [] Trans- +
porter
• Not very selective and thus 2 different drugs can compete for
each other. At Equilibrium:
• Transport proteins are required to couple the input of energy to C2 > C1
+ +
the movement of the drug
• Transported species may have a net charge
- Consequently, unlike diffusion through the bilayer, transport only occurs in cells that express the required transport
– Charged forms of bases, anions of acids, fixed charge
proteins – Permanently charged quaternary drugs
• MECHANISMS – key things to remember • Drugs with same charge can compete with each other
- Cells have a Na/K ATPase in plasma membrane
o This pump generates Na+ (inward) and K+ (outward) gradients across the plasma membrane
o This pump in conjunction with K+ channels generates a positive outside electrical membrane potential
- These gradients drive transport of drugs

Hold on! Wait a minute!


• Someone has a question...
- You started off arguing that because drugs, unlike physiological substances don’t have transporters to get into the
body, they must have good partition coefficients.
- Now you are saying there are transporters for drugs!
- I am confused, what’s the deal????
• Answer: Role of these transporters is to protect the body against xenobiotics...

ROLES of TRANSPORTERS
• Role is to protect the body against xenobiotics
• Transporters in liver, kidney and intestine epithelia have roles in absorption and elimination
• Transporters in tissues such as brain, testis, placenta also help prevent entry of harmful xenobiotics, but also can limit
distribution of therapeutic drugs to those tissues

Drug Transporters
• Most drug and xenobiotic transporters come from two “super-families” of transporters
1) SLC (SoLute Carrier) transporters, includes 315 transporters in 48 families
2) ABC (“ATP Binding Cassette”) transporters, includes 49 different transporters in 7 families
• Substrate selectivity is broad, allows transport of many xenobiotics, clinical significance:
- Drug interactions between competing drugs that have similar properties, e.g. same charge

Where Does Active Transport Take Place?


• The physiological role of these transporters is to protect the body against xenobiotics, and this explains their locations in
the body
1. Proximal tubule of kidney nephron – Important for excretion of some drugs
2. Hepatocytes, GI tract

• Transporters in liver and intestine epithelia are most important for drug absorption and elimination

- Important for drug transport into cells for biotransformation
- Important for drug transport out of cells into bile or blood

Where Does Active Transport Take Place?


3. Vascular endothelium in brain, choroid plexus (barrier between blood and CSF), as well as other locations, e.g. testis,
placenta
• Protects tissue by pumping drugs out of tissue into the blood limiting drug distribution and minimizing potential harm
• Can be a problem when we need to get a drug into the brain, e.g. to treat an infection

Summary: TYPES of MEMBRANE TRANSPORT


• Diffusion across lipid membranes
- uncharged drugs with “favorable” partition coefficient
- weak acids and bases with “favorable” partition coef.
o Effect of pH gradient - “ion trapping”
• Pores in capillaries (filtration/diffusion)
• Active Transport
- Active cation, anion and neutral drug transporters (require energy) are present in kidney tubules, liver cells, GI tract,
blood brain barrier and choroid plexus