Download Principles of Pharmacology

Regulation of Drug Transport, Absorption,
Distribution, Excretion and Metabolism
Dennis Paul, Ph.D.
Department of Pharmacology
504-568-4740
[email protected]
Principles of Pharmacology
Common processes and mechanisms
whereby:
• Drugs gain access to the body
• Drugs move throughout the body
• Drugs produce an effect by altering
a physiological process
• Drugs are removed from the body
Pharmacokinetics
The study of drug movement into, within and out of
the body, which includes absorption, distribution,
metabolism and elimination
•Pharmacokinetics:
•Absorption: Transfer of drug from site
of administration to systemic circulation
•Distribution: Transfer of drug from
systemic circulation to tissues
•Metabolism: Alteration of drug to
increase excretion from the body
•Excretion: Drug movement out of the
body
Routes of drug administration
Affects onset and duration of drug
1) Enteral – directly into G.I. tract
Oral or rectal administration
- safest, cheapest, most convenient
- slow onset, sometimes unpredictable response
2) Parenteral – bypasses G.I. tract
Usually injection, can be inhalation or topical administration
- fast absorption, rapid onset, predictable response
- more expensive, more difficult, painful, requires
sterile conditions
Oral route (enteral)
● Advantages
-Most common, convenient, painless and inexpensive way to
administer a variety of drugs e.g. liquid, tablet, coated tablet
etc
-GI tract a large blood rich absorbent surface
● Disadvantages
-First pass metabolism Drug must pass through GI tract and
liver before entering circulation and therefore are subject to
metabolism meaning higher doses are given orally e.g.
morphine
-Food and GI motility affects absorption – must comply with
instructions e.g. with food or on empty stomach
-Can be difficult to predict percentage of active drug
that reaches patient
Rectal route (enteral)
 Usually suppository, cream or enema e.g. aspirin,
barbituates
 Drug mixed with waxy substance that dissolves in the
rectum
Advantages
-Reduced first pass metabolism, some rectal veins lead
into direct circulation bypassing liver
-Used in patients unable to take drugs orally e.g. elderly,
young, unconscious
Disadvantages
-Not well liked by patients
-Absorption very variable so not reliable method of drug
delivery
Drug Profiles
90
[Drug]
80
70
60
50
40
30
20
10
0
0
10 20 30
40 50 60
70 80 90 100
Time (h)
Physical Properties
Structure
Lipid solubility
Ionization state
Objectives
I.
II.
III.
IV.
V.
Mechanisms of drug transport
Drug absorption
Drug distribution
Drug metabolism
Drug excretion
Mechanisms of Drug Transport
1.Passive diffusion
a. Passive diffusion of non-electrolytes
b. Passive diffusion of electrolytes
2.Filtration
3.Carrier-mediated transport
a. Active transport
b. Facilitated diffusion
4.Receptor-mediated endocytosis
5.Ion-pair transport
Endogenous compounds and drugs
Mechanisms of Drug Transport
1. Passive diffusion – Low molecular weight drugs that
are both water and lipid soluble dissolve in
membrane and cross to the other side.
Primary means by which drugs cross membranes
Mechanisms of Drug Transport
• Passive Diffusion
• Drugs dissolve and cross the cell membrane following
concentration gradient.
• Characteristics of drugs that use passive diffusion:
● Small
● Predominantly lipid soluble
● Uncharged
● Small water soluble molecules pass via pores
Mechanisms of Drug Transport
1. Passive diffusion
1) Passive diffusion of non-electrolytes
2) Passive diffusion of electrolytes
– Influence of pH and pka
– Weak acids are uncharged in acidic
environment
– Weak bases are uncharged in basic
environment
Mechanisms of Drug Transport
1. Passive diffusion
1) Passive diffusion of non-electrolytes
Lipid-water partition coefficient (Kp) - the ratio of the concentration of
the drug in two immiscible phases: a nonpolar liquid (representing
membrane) and an aqueous buffer (representing the plasma).
Kp can be measured. Kp = [drug] in lipid phase/[drug] in aqueous
phase.
If the drug is more soluble in the lipid, Kp is higher. If the drug is more
soluble in the aqueous phase, Kp will be lower.
The partition coefficient is a measure of the relative affinity of a drug for
the lipid and aqueous phases.
One can control the Kp by modifying the side groups on the compound.
The more C and H on the compound, the more lipid soluble, and thus
the higher the Kp. The more O, S and the more water-soluble the
compound, and the lower the Kp.
Mechanisms of Drug Transport
Passive diffusion of non-electrolytes:
The higher the Kp, the more lipid
soluble, the faster the rate of
transfer across biological
membranes
Mechanisms of Drug Transport
2) Passive diffusion of electrolytes
pKa: the pH at which half of the molecules are in the
ionized form and one half are in the unionized form.
pKa is a characteristic of a drug.
Henderson-Hasselbalch equations:
For acids: pH = pKa + log [A-]/[HA]
For bases: pH = pKa + log [B]/[BH+]
Mechanisms of Drug Transport
2) Passive diffusion of electrolytes
HA
H+ + A-
BH+
H+ + B
pH < pKa
Predominate forms:
HA and BH+
pH
3
4
pH > pKa
pH = pKa
5
HA = ABH+ = B
6
7
Predominate forms: A- and B
8
9
10
11
Mechanisms of Drug Transport
2) Passive diffusion of electrolytes
Only the unionized forms of the drug or the uncharged drug can
pass through or across the membranes (or is transferred) by
passive diffusion.
- Un-ionized form acts like a nonpolar lipid soluble compound
and can cross body membranes
- Ionized form is less lipid soluble and cannot easily cross
body membranes
By controlling the pH of the solution and/or the pKa of the
drug, you can control the rate at which the drug is
transferred
Mechanisms of Drug Transport
- Drugs that are weak electrolytes equilibrate
into ionized and non-ionized forms in solution
- pH (H+ concentration) at site of administration
and the dissociation characteristics (pKa) of
the drug determine the amount ionized and
non-ionized drug
Mechanisms of Drug Transport
ASPIRIN pKa = 4.5 (weak acid)
100mg orally
H+ + A- 1 = [ I ]
Stomach
pH = 2
Blood
pH = 7.4
99 = [ UI ]
HA
Aspirin is absorbed from stomach (fast action)
Mechanisms of Drug Transport
Aspirin accumulation
Acidic drug - pKa = 4.5
[ UI ]
1
HA
pH = 2
Body compartment 1 - stomach
[I]
0.01
H+ + A-
Membrane
Body compartment 2 – blood
pH = 7.4
HA
1
[ UI ]
H+ + A-
100
[I]
Mechanisms of Drug Transport
STRYCHNINE pKa = 9.5 (weak base)
100mg orally
H+ + B
99 = [ I ]
Stomach
pH = 2
Blood
pH = 7.4
1 = [ UI ]
HB+
Strychnine not absorbed until enters G.I. tract
Mechanisms of Drug Transport
2. Filtration
- Passage of molecules through membrane
pores or porous structures.
Mechanisms of Drug Transport
The rate of filtration
a. Driving force: The pressure gradient in both
sides.
b. The size of the compound relative to the size
of the pore.
i. Smaller compound – transfer rapidly
ii. Larger compound – retained
iii. Intermediate compound – barrier
Lipid soluble – passive diffusion
Water soluble – filtration
Mechanisms of Drug Transport
The rate of filtration:
In biological systems: Filtration is the transfer of drug across
membrane through the pores or through the spaces between cells
a. Capillary endothelial membranes
b. Renal glomerulus
• Most substances (lipid-soluble or not) – cross the capillary wall – very fast
• Lipid soluble and unionized – filtration and passive diffusion – at the same time
Mechanisms of Drug Transport
•
3. Carrier-mediated transport
A. Active transport
- Goes against concentration gradient
- Requires energy (ATP)
- Mediated by transport carrier proteins
- Drug combines with a transport protein in the
membrane and the complex can move across the
membrane
a. Selectivity - not for all drugs
b. One-way process – against drug concentration gradient
resulting in drug accumulation
c. It can be saturated – Drug/receptor ratio – enzyme-catalyzed
reactions
d. Can be inhibited – ATP inhibitors, structural analogous
compounds
Mechanisms of Drug Transport
3. Carrier-mediated transport
b. Facilitated diffusion
a.
b.
c.
d.
e.
f.
Carrier or receptor-mediated
Selective to specific molecules e.g. glucose
It can be saturated
Does not require ATP
Does not go against the concentration gradient
Bi-directional – no drug accumulation
Mechanisms of Drug Transport
4. Receptor-mediated endocytosis
- more specific uptake process
Drugs (peptide hormones, growth factors, antibodies, et al.)
bind to their receptors on the cell surface in coated pits, and
then the ligand and receptors are internalized, forming
endosomes.
Receptor-ligand complex may take four different pathways:
a.
b.
c.
d.
Receptor recycles, ligand degraded
Receptor and ligand recycle
Receptor and ligand degraded
Receptor and ligand transported
Mechanisms of Drug Transport
5. Ion-pair transport
Highly ionized
Passive diffusion
+
+
+
_
Carrier
_
+
_
_
Pharmacokinetics: Absorption
• Process by which drug
molecules are transferred from
administration site to systemic
circulation
• Factors affecting absorption:
1. site of GI absorption
2. modifications
• Bioavailibility
• Solubility of drug e.g. suspension absorbed
more slowly than a solution, solubility =
absorbance
Drug Absorption
1. Sites of absorption through the GI tract
1) Mouth
2) Stomach
3) Small intestine
4) Large intestine
Drug Absorption
1) Mouth:
a. Small amount of surface area but good blood flow –
best for potent drugs.
b. Transfer by passive diffusion – good for lipid soluble
drugs.
c.
pH = 6. Weak base drugs have better absorption.
Nicotine pKa 8.5
pH
Ionization
Absorption
Mouth
6
less ionized
4 times faster
d. Can bypass first pass effect.
GI tract
1-5
ionized
Drug Absorption
2) Stomach:
a. Moderate surface area – more than mouth, less than small
intestine.
b. Good blood supply.
c.
Drugs absorbed in the stomach will experience first pass effect.
d. Transfer by passive diffusion.
e. Low pH (1-2) – ionization - Drugs that are weak acids will be
absorbed better than weak base drugs.
f.
Ion trapping: Accumulation of weak base drugs in the stomach.
Drug Absorption
3) Small intestine
a. The primary site for most drugs.
b. Large surface area - Folds, villi and microvilli.
c. pH = 5-8.
d. Passive diffusion.
e. Absorption can also take place by active
transport, facilitated diffusion, endocytosis and
filtration.
Drug Absorption
4) Large intestine
a. Not important for drug absorption, if the drug
is absorbed effectively in small intestine.
b. Can be a site of absorption for incompletely
absorbed drugs.
c. Less absorption then small intestine – less
area and solid nature of contents.
Drug Absorption
2. Factors that modify absorption in the GI tract
1) Drug solubilization
2) Formulation factors
3) Concentration of drug at the absorption site
4) Blood flow at the absorption site
5) Surface area of absorption small intestine
6) Route of administration
7) Gastric emptying
8) Food
9) Intestinal motility
10) Metabolism of drug by GI tract
Drug Absorption
1) Drug solubilization – breaking drugs into smaller, more
absorbable particles
Hydrophilic drugs - poorly absorbed - inability to cross the lipid-rich cell
membrane.
Hydrophobic drugs - poorly absorbed - insoluble in the aqueous body fluids
- cannot gain access to the surface of cells.
- largely hydrophobic yet have some solubility in aqueous solutions.
Solid
Granules
fine particles:
disintergration
deaggregation
Solution
Drug Absorption
2) Formulation factors – materials added to the drug during
processing can affect the solubilization of the drug.
a. Fillers – add bulk to the tablet
b. Disintegrators – cause table to break down into granules
c. Binders – hold tablet together
d. Lubricants – prevent tablet from sticking to machinery
Formulation factors - not clinically important if the drug is absorbed effectively and may
have important influence on drug absorption for these drugs which are not effectively
absorbed in the GI tract - influence drug’s bioavailability.
Drug Absorption
3) Concentration of drug at the absorption site
Passive diffusion
Driving force – the concentration gradient.
The higher the concentration of the drug, the
faster the rate of absorption.
Drug Absorption
4) Blood flow at the absorption site
- maintain concentration gradient
Membrane
Blood
Drug Absorption
5) Surface area of absorption small intestine
Drug Absorption
6) Route of administration
GI tract – first pass effect
Drug Absorption
7) Gastric emptying
small intestine – primary site of drug absorption
Anything that delays/accelerates gastric emptying
will decrease/increase drug absorption.
For all drugs - acidic, basic or neutral substances.
Drug Absorption
8) Food
High fat food – delay gastric emptying –
slow absorption
Drug Absorption
9) Intestinal motility
– depends on whether the drug is completely
absorbed under normal condition.
a. Completely absorbed early upon entry into the
small intestine, increasing intestinal motility will
not significantly affect absorption.
b. Not completely absorbed before entry into the
small intestine, increasing/decreasing intestinal
motility will slow down/facilitate drug absorption.
Drug Absorption
10) Metabolism of drug by GI tract
a. Drug metabolizing enzymes in the GI tract
b. Proteases in the GI tract
c. Microbes in the GI tract - metabolize certain
drugs
- Drug metabolites are not usually absorbed.
Absorption: Bioavailability
– Bioavailability: fraction of oral dose that
appears in systemic circulation.
• Unless given as liquid, drug must be
released by:
- Disruption of coating or capsule
- Disintegration of tablet
- Dispersion throughout stomach or G.I.
tract
- Dissolution in gastrointestinal fluid
Absorption: Bioavailability
Pharmacokinetics: Drug Distribution
• The dispersion or dissemination of
substances throughout the fluids e.g. plasma,
intracellular fluids and tissues of the body.
• 2 drug forms:
- free (pharmacologically active), can cross cell
membranes
- bound to plasma proteins (pharmacologically
inactive)
Pharmacokinetics: Drug Distribution
Factors affecting distribution:
- Plasma proteins
- Blood flow to tissues
- Specialized barriers
- pH differences between plasma and tissue
compartments
- Lipid solubility vs. water solubility
Drug Distribution
Volume of distribution (Vd): A hypothetical volume of fluid
into which the drug is distributed.
- Water compartments in the body - three functionally
distinct water compartments – plasma, interstitial
fluid and intracellular fluid.
Total body water
60% of body weight
60% x 70 kg = 42 liters
Intracellular fluid
40% of body weight
28 liters
Extracellular fluid
20% of body weight
14 liters
Plasma
6% of body weight
4 liters
Interstitial volume
14% of body weight
10 liters
Drug Distribution
Plasma compartment: Large molecular
weight or binds extensively to plasma
proteins - trapped in the plasma
compartment – Vd = 4 liters.
Extracellular fluid: Low molecular
Plasma
4L
Intracellular
28 L
Interstitial fluid
10 L
weight, hydrophilic - able to move
through fenestrae into the interstitial
fluid, but cannot move across the cell
membranes into the intracellular fluid sum of the plasma water and interstitial
fluid – Vd = 14 liters.
Total body water: Low molecular weight,
hydrophobic - move into the interstitial
fluid and the intracellular fluid – Vd =
42 liters.
Drug Distribution
Drug Distribution
Regional blood flow – unequal distribution of
cardiac output
Perfusion rate: blood flow to tissue mass ratio
Higher: heart, kidney, liver, lung and brain
Moderate: muscle and skin
Low: adipose tissue
The perfusion rate affects the rate at which a drug reaches the
equilibrium in the extracellular fluid of a particular tissue.
The greater the blood flow, the more rapid the drug distribution from
plasma into interstitial fluid. Therefore, a drug will appear in the
interstitial fluid of liver, kidney and brain more rapidly than it will in
muscle and skin.
Drug Distribution
Capillary permeability
Drug transfer through capillary – filtration
a. Capillary structure: Capillary size and fenestrae size
Liver: larger fenestrae - greater filtration potential
Brain: smaller fenestrae – lower capillary permeability
Liver – slit junction
Brain – tight junction -blood-brain barrier
Drug Distribution
Specialized barriers
-Blood-brain barrier (cell layer and basement membrane)
To penetrate CNS drug must cross BBB, which consists of
epithelial and basement membrane cells
Are no pores, gaps etc to allow easy penetration of drugs
Drug penetration of BBB relates to lipid solubility and ionization
Highly lipid soluble non-ionized drugs easily penetrate BBB to
access cerebrospinal fluid e.g. thiopental
Highly lipid insoluble and/or ionized drugs in general do not cross
BBB and do not affect CNS e.g. hexamethomium
-Placenta
Drugs pass via simple diffusion governed by lipid solubility
↑ lipid solubility = ↑ drug uptake by fetus
Most drugs taken by mother reach the fetus e.g. alcohol
Drug Distribution
Blood-brain barrier
Liver
Brain
Large fenestrae
Slit junction
Slit junction Drugs
Tight junction
Small fenestrae
Lipid soluble drugs
Passive diffusion
Carrier-mediated
transport
Endothelial cells
MEMBRANE
MEMBRANE
Drug Distribution
Capillary permeability
Drug transfer through capillary – filtration
a. Capillary structure:
b. Chemical nature of the drug:
Sizes of the drug
Drug structure:
Hydrophobic drugs: passive diffusion – blood flow
Hydrophilic drugs – fenestrae - filtration
Drug Distribution
Rate of transfer from interstitial fluid into tissues
Passive diffusion, active transport and
endocytosis.
Passive diffusion - the most common and
quickest means
Blood – plasma
Interstitial fluid
Drug Distribution
Binding to plasma proteins - reversible
Capillary endothelium cells
Blood
Interstitial fluid
Cells and tissues
Drug Distribution
Consequence of drug binding to plasma
proteins:
Cannot go to its receptor at the site of action
Cannot be distributed to body tissues
Cannot be metabolized by enzymes
Cannot be excreted from the body
Drug Distribution
- Bound drugs are pharmacologically inactive.
- Drug binding to plasma protein will delay the
onset of drug action.
- Drug binding to plasma proteins will
decrease the intensity of drug action.
Drug Distribution
Drug binding to plasma proteins may prolong drug
action.
Reservoir of non-metabolized drug in the body
Surmin – trypanosomiasis – A single IV injection may
be effective for three months.
Warfarin – 97% bound to plasma proteins and 3%
free.
Drug Distribution
Types of plasma proteins:
Albumin:
• The primary serum protein responsible for drug
binding
• 68 kD
• The strongest affinity for weak acid and
hydrophobic drugs.
• 1 or 2 selective high affinity binding sites for week
acidic drugs.
Drug Distribution
Types of plasma proteins:
Lipoproteins:
• Lipid-soluble drugs
• The binding capacity is dependent on their lipid
content.
• Binding ability of lipoproteins is VLDL > LDL >
HDL.
• Patient – more free drug available for
absorption in patients with high HDL than
patients with high LDL.
Drug Distribution
Types of plasma proteins:
alpha1-acid glycoprotein:
•
•
•
•
Alpha1- globulin
44KD
One high affinity binding site and binds only basic drugs
Plasma concentration - inducible by acute injury, trauma,
and stress.
• The half time: 5.5 days.
• Patient with trauma taking a basic drug – side effect
More plasma proteins
Less free drug available
Drug Distribution
Plasma Half-life (t1/2)
Amount of time required for the concentration of a drug to fall
to one half of its blood level
-When half-life is short drug is quickly removed and duration
of action is short e.g. t1/2 = 1h drug mostly gone in 4-5 hours
-When drug half-life is long drug slowly removed from body
and duration of action is long e.g. t1/2 = 60 h drug needs 300 h
to be mostly gone from body
First order
kinetics
t1/2
100%
t1/2
50%
t1/2
25%
t1/2
12.5%
t1/2
6.25%
3.13%
Drug Metabolism
• Metabolism: Irreversible biochemical
transformation of drug into metabolites to increase
excretion from the body via the kidney
-
-
Metabolism/Biotransformation occurs mainly in the liver
Usually drug is converted to a more water soluble compound
Activity of metabolite may be different from parent compound
Metabolite usually more polar (ionized)
Metabolite usually less lipid soluble
Renal tubular absorption of metabolite 
Metabolites less likely to bind to plasma proteins
Metabolites less likely to be stored in fat
Drug Metabolism
The liver is the dominant organ in drug metabolism
Organ
Relative activity (%)
Liver
Lung
Kidney
Intestine
Placenta
Adrenal
Akin
Leukocytes
Spleen
Eye
brain
100
20-30
8
6
5
2
1
lower
lower
lower
lower
Drug Metabolism
Mechanisms of drug metabolism
1) Active drug  inactive metabolite, most common
metabolic reaction e.g. doxycyline
2) Inactive drug  active drug, prodrug converted to
active drug e.g. acyclovir
3) Active drug  active metabolite, adds another step
before excretion and prolongs drugs actions e.g.
diazepam to active metabolite desmethyldiazepam
Drug Metabolism
• First pass effect
– Drugs taken orally pass through the liver before they get to the
systemic circulation.
– During first pass through the liver, drug is removed by
metabolism or hepatobiliary secretion.
– Phase I, oxidation, hydrolysis and reduction (non-synthetic
reactions)
– Phase II, conjugation (synthetic reactions)
– Forms easily excreted polar compound
If no functional group
Drug
Phase I
metabolite
Phase II
If drug has functional group
Drug
Phase II
excretion
excretion
Drug Metabolism
Phase I metabolism
-Metabolizes drugs to creates sites for phase II metabolism
1) Oxidation (adds O) typically via simple addition of O or
hydroxylation (adds H and O). Mediated predominantly via
microsomal endoplasmic reticulum cytochrome P450 liver
enzymes. Kidney and nervous tissue enzymes can also oxidize
compounds
2) Reduction (gain of electron or H). Mediated by P450 enzymes
3)Hydrolysis (addition of water). Performed by hydrolytic enzymes
called plasma esterases e.g. plasma cholinesterase
Drug Metabolism
I. Types of non-synthetic reactions
1. Oxidation reactions
A.
B.
C.
D.
A direct insertion of a hydroxyl functional group into the drug
molecule
Mostly by cytochrome P450
Almost exclusively in the ER
Broad specificity of cytochrome P450 – multiple isoforms
The hepatic microsomal cytochrome P450-dependent electron transfer
chain
NADPH
NADP+
NADPH
Cytpchrome
P450
reductase
RH + O2
P450
ROH + H2O
RH – drug substance
Drug Metabolism
I. Types of non-synthetic reactions
1. Oxidation reactions
A.
B.
C.
D.
E.
F.
A direct insertion of a hydroxyl functional group into the drug molecule
Mostly by cytochrome P450
Almost exclusively in the ER
Broad specificity of cytochrome P450 – multiple isoforms
Types of microsomal oxidations
1) Aromatic or ring hydroxylation
2) Aliphatic hydroxylation
3) Epoxidation
4) N-, O-, and S-dealkylations
5) N-hydroxylation (not P450)
6) N-oxidation (not P450)
7) Oxidative deamination
8) Sulfoxide formation
9) Desulfuration
Non-microsomal oxidation
1) Alcohol dehydrogenase
2) Aldehyde dehydrogenase
3) Xanthine oxidase
4) Tyrosine hydroxylase
5) Monoamine oxidase
Drug Metabolism
I. Types of non-synthetic reactions
1. Oxidation reactions
A.
B.
C.
D.
E.
F.
A direct insertion of a hydroxyl functional group into the drug molecule
Mostly by cytochrome P450
Almost exclusively in the ER
Broad specificity of cytochrome P450 – multiple isoforms
Types of microsomal oxidations
1) Aromatic or ring hydroxylation
2) Aliphatic hydroxylation
3) Epoxidation
4) N-, O-, and S-dealkylations
5) N-hydroxylation (not P450)
6) N-oxidation (not P450)
7) Oxidative deamination
8) Sulfoxide formation
9) Desulfuration
Non-microsomal oxidation
1) Alcohol dehydrogenase
2) Aldehyde dehydrogenase
3) Xanthine oxidase
4) Tyrosine hydroxylase
5) Monoamine oxidase
Drug Metabolism
Aromatic hydroxylation
Drug Metabolism
Aromatic hydroxylation
Drug Metabolism
Aliphatic hydroxylation
Drug Metabolism
Epoxidation
Drug Metabolism
Oxidative deamination
Drug Metabolism
I. Types of non-synthetic reactions
2. Reduction reactions - gain of electron or H
A. Catalyzed by reductases
B. Reductases - found in microsomes, the
cytosol and microorganisms in the gut
Drug Metabolism
I. Types of non-synthetic reactions
1. Oxidation reactions – mostly by cytochrome P450
2. Reduction
3. Hydrolysis
A. Breaking compounds with the addition of water
B. Primarily occur in the liver, kidney and in the plasma
C. Esterase – carry out the major hydrolysis reactions
D. Amidase and expoxide hydrolases
Drug Metabolism
Hydrolysis catalyzed by esterases
Addition of H2O
Drug Metabolism
Hydrolysis catalyzed by amidases
Addition of H2O
Drug Metabolism
I. Non-synthetic reactions
II. Synthetic reactions – conjugation reactions
couples agent to existing (or phase I formed) conjugation site on drug/metabolite
Involves addition to functional groups including ethers, alcohols, aromatic amines
on drug metabolite
• Glucuronidation - the most common reaction, occurs in the liver, Glucaroninc
acid combines with -OH, -SH, -COOH, -CONH groups to create glucuronide
metabolites
• Sulfate conjugation - the second important reaction, catalyzed by
sulfotransferases in the cytoplasma of the liver and other organs
• Acetylation - catalyzed by N-acetyltransferases. Acetic acid combines with NH2, -CONH2 groups and aminoacids to give acetylated derivatives
• Methylation - catalyzed by methyltransferases in the cytoplasma or ER
• Glutathione conjugation - Glutathione combines with -nitrate, epoxide and
sulphate groups to create glutathione conjugates
• Amino acid conjugation - add naturally occurring amino acids prior to secretion
Drug Metabolism
Two pathways of conjugation reactions
Drug Metabolism
Factors affecting drug metabolism
1. Age
2. Nutrition and diet
3. Enzyme induction and inhibition by foreign compounds
Induction
Increase amount/activity of P-450 enzymes
Many different compounds are able to alter isoenzyme
activity
 P-450  drug metabolism and  drug effect
e,g, Phenobaritol stimulates CYP P-450 metabolisim of
warfarin and reduces warfarin effect
Inhibition
Decreases amount/activity of P-450 enzymes
 P-450  drug metabolism and  drug effect
Drug Excretion
• Excretion: The elimination of the substances from
the body unchanged or as a metabolite.
1. Sites for drug excretion:
1)
2)
3)
4)
5)
Kidney - Urine
Liver – Bile
Skin
Lung
Milk
Drug Excretion
1. Renal excretion
Glomerular filtration
Drug/metabolite filtered via glomeruli
and concentrated in renal tubular fluid
and excreted in urine.
Protein bound drug remains in systemic
circulation.
•
•
•
•
•
Drugs from glomerulers into the renal
tubules
Pressure – blood flow
MW cut off = 5000
7500 – restricted
Lipid soluble drugs – also by passive
diffusion
Drug Excretion
2. Renal excretion
1) Glomerular filtration
2) Active secretion
•
Two active transport systems:
Organic acids
Organic bases
•
Relatively non-specific
•
Unidirection – accumulation and
excretion
Drug Excretion
2. Renal excretion
1)
Glomerular filtration
2)
Active secretion
3)
Passive reabsorption - Affected by urinary pH
•
Unionized, lipid soluble metabolites are
reabsorbed
•
Ionized, lipid-insoluble metabolites excreted in
urine
More ionization – more secretion
Forced alkaline diuresis
Phenobarbital – weak acid
Renal tubule pH = 5 – 8
-Alkaline urine = increased weak acid excretion,
reduced weak base excretion
-Acidic urine = decreased weak acid excretion,
increased weak base excretion
Bicarbonate–increase pH–ionized–faster excretion
Ammonium chloride – decrease pH
Excretion
Drug Excretion
Kidneys
3. Secretion from the liver:
Liver - Bile – intestine
•
Liver:
Metabolizing enzymes
Active transport systems – bile capillaries
•
Lipid insoluble or ionized drugs – excretion
•
Lipid soluble – reabsorption from intestine to bile – transport back to the liver Enterohepatic cycling:
Prolong drug action
Conserve endogenous substances – VD3,B12, folic acid, estrogens.
Drug Excretion
4. Pulmonary excretion
Gasses and volatile liquids
Simple diffusion from the blood into the airway
Drug Excretion
5. Sweat and saliva
Drugs or drug metabolites
Passive diffusion
Side reaction of the skin
Drug Excretion
6. Milk
Passive diffusion
Not very important for mother
May be important for infant