Transcript Absorption, distribution, metabolism and excretion

Pharmacokinetics, Overview
 Pharmacokinetics: the study of the movement of drugs in the body, including the processes of
absorption, distribution, localization in tissues, biotransformation and excretion
 Learning pharmacokinetics is of great practical importance in the choice and administration of a
particular drug for a particular patient, e.g., one with impaired renal function
Pharmacokinetics, Introduction
 Drugs need to achieve an adequate concentration in their target tissues.
 The two fundamental processes that determine the concentration of a drug at any
moment and in any region of the body are:
– translocation of drug molecules
– chemical transformation by drug metabolism and other processes involved in drug elimination
 These are critically important for choosing appropriate routes of administration
 Translocation of drug molecules: drug molecules move around the body in two
ways:
 bulk flow transfer (i.e. in the bloodstream)  The chemical nature of a drug makes no difference
to its transfer by bulk flow.
 diffusional transfer (i.e. molecule by molecule, over short distances)
 Diffusional transfer (transmembrane movement of the drugs):
 ability to cross hydrophobic diffusion barriers is strongly influenced by lipid solubility.
 delivering drug molecules to and from the non-aqueous barriers is influenced by water solubility
The Movement of Drug Molecules Across Cell Barriers
 Gaps between endothelial cells are packed with a loose matrix of proteins that act as filters,
retaining large molecules and letting smaller ones through.
 In some organs (e.g. the liver and spleen) endothelium is discontinuous, allowing free
passage between cells.
 Aqueous Diffusion: It occurs within the larger
aqueous compartments of the body (interstitial space,
cytosol, etc) and across epithelial membrane tight
junctions and the endothelial lining of blood vessels
through aqueous pores.
 It is probably important in the transfer of gases such as carbon
dioxide
 In other organs, especially in the CNS (blood brain barrier) and the placenta (placental
barrier),
 There are tight junctions between the cells
 the endothelium is enclosed in an impermeable layer of periendothelial cells (pericytes).
 These features prevent potentially harmful molecules from leaking from the blood into these
organs and have major pharmacokinetic consequences for drug distribution.
The Movement of Drug Molecules Across Cell Barriers
 Passage of drugs across cell membranes
1) Passive transfer:
a. Simple diffusion: The vast majority of drugs gain access to the body through this mechanism.
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Drugs must be first in aqueous solution to gain access to the lipid membrane
Drugs pass along concentration gradient
No energy or carrier is required
It is not inhibited by metabolic inhibitors
It is not saturable.
It depends on:
 concentration gradient
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lipid solubility
degree of ionization,
thickness of membrane
molecular size.
 Concentration gradient is maintained by removal of the drug from other side of the
membrane.
 Lipid solubility is measured by lipid/water partition coefficient (ratio of drug concentration in
lipid phase and water phase when shaken in one immiscible lipid/water system). Ionized
drugs generally have low lipid/water coefficient.
The Movement of Drug Molecules Across Cell Barriers,
Lipid solubility: weak acids and weak bases/Clinical Significance
Ka
Ka
HA <==> H+ + A-
BH+ <==> B + H+
[UI]
[I]
[I]
pKa=pH+log(HA/A-)
ASPIRIN pKa = 3.5 (weak acid)
100mg orally
0.1 = [ I ]
Stomach
pH = 2
99.9 = [ UI ]
Blood
pH = 7.4
[ UI ]
Aspirin is reasonably absorbed
from stomach (fast action)
[UI]
pKa=pH+log(BH+/B)
STRYCHNINE pKa = 8.0 (weak base)
100mg orally
99.9 = [ I ]
Stomach
pH = 2
0.1 = [ UI ]
Blood
pH = 7.4
[ UI ]
Strychnine is not absorbed until
enters duodenum
The Movement of Drug Molecules Across Cell Barriers,
Lipid solubility: weak acids and weak bases/Clinical Significance, contd.
 In drug poisoning, renal elimination of drugs can be enhanced by changing urinary
pH to increase drug ionization and inhibits tubular re-absorption.
 Alkalinization of urine by NaHCO3 increases excretion of acidic drugs e.g. aspirin.
 Acidification of urine by vitamin C or NH4Cl increases excretion of weak base drugs e.g.
amphetamine.
The Movement of Drug Molecules Across Cell Barriers,
contd.
b. Filtration: In capillaries, pores have large size and so nearly all free drugs in plasma can
be filtered. It depends on hydrostatic and osmotic pressure, so it is limited by blood flow but
not by lipid solubility and it is not saturable
2) Specialized transport:
- Substances that are too large or poorly lipid soluble as amino acids and glucose are carried by specialized
carriers.
- a. Facilitated diffusion: is similar to simple diffusion but requires a carrier and it is saturable.
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A carrier molecule is a
transmembrane protein which
binds one or more molecules or
ions, changes conformation and
releases them on the other side
of the membrane.
- Carrier molecules facilitate
entry and exit of physiologically
important molecules, such as
sugars, amino acids,
neurotransmitters and metal in
the direction of their
electrochemical gradient
The Movement of Drug Molecules Across Cell Barriers,
contd.
b. Active transport: where drugs pass against concentration gradient, so it requires:
 energy,
 carrier (thus it is saturable)
 Example: many drugs, especially weak acids (e.g., penicillin, uric acid) and weak bases (e.g.,
histamine), are actively secreted into the renal tubule, and thus more rapidly excreted
Mechanism
Direction
Energy required
Carrier
Saturable
Passive diffusion
Along gradient
No
No
No
Facilitated diffusion
Along gradient
No
Yes
Yes
Active transport
Against gradient
Yes
Yes
Yes
The Movement of Drug Molecules Across Cell Barriers,
contd.
c. Pinocytosis: It involves
 invagination of part of the cell membrane and the trapping of a small vesicle containing
extracellular constituents within the cell
 The vesicle contents can then be released within the cell, or extruded from its other side
 Examples:
 Pinocytosis of vitamin B12 (complexed with intrinsic factor).
 It is important for the transport of some macromolecules (e.g. insulin, which crosses the blood–brain
barrier by this process)
Plasma level curve
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Cmax = maximal drug level obtained with the dose.
tmax = time at which Cmax occurs.
Lag time = time from administration to appearance in blood.
Onset of activity = time from administration to blood level reaching minimal effective concentration
(MEC).
Duration of action = time plasma concentration remains greater than MEC.
Time to peak = time from administration to Cmax.
1- Absorption
 It is the process of entry of drug from site of administration into systemic circulation.
 Factors influencing absorption
 A- Factors related to drug
a) Physicochemical properties:
1-Degree of ionization: highly ionized drugs are poorly absorbed.
2-Degree of solubility: High lipid/water partition coefficient increases absorption.
3-Chemical nature: inorganic iron is better absorbed than organic iron.
4-Valency: ferrous salts are more absorbed than ferric,
-so vitamin C increases absorption of iron.
b) Pharmaceutical form of drug:
Absorption of solutions is better than suspensions or tablets.
1- Absorption, Factors Influencing Absorption, contd
 B- Factors related to the patient:
1-Route of administration:
absorption is faster from i.v. > inhaled > i.m. > oral > dermal administration
seconds
minutes
hours
2-Area and vascularity of absorbing surface:
absorption is directly proportional to both area and vascularity. Thus absorption of
the drug across the intestine is more efficient than across the stomach, as intestine
has more blood flow and much bigger surface area than those of the stomach
3-State of absorbing surface: e.g. atrophic gastritis and mal-absorption syndrome
decrease rate of absorption of drugs.
4-Rate of general circulation: e.g., in shock, peripheral circulation is reduced and
I.V. route is used.
5-Specific factors and presence of other drugs: e.g. intrinsic factor of the stomach
is essential for vitamin B12 absorption from lower ileum and adrenaline induces
vasoconstriction so delay absorption of local anesthetics.
Bioavailability
 It is the fraction of drug that reaches systemic circulation in an unchanged form and
becomes available for biological effect following administration by any route. It is 100%
after IV administration.
 It is calculated by comparison of the area under the plasma concentration time curve
(AUC) after IV dose of a drug with that observed when the same dose is given by another
route e.g. oral.
Area under the curve (AUC) oral x 100
Oral bioavailability =
Area under the curve (AUC) I.V.
 Oral bioavailability depends on amount absorbed
and amount metabolized before reaching systemic
circulation (first pass metabolism)
 Bioequivalence:
 Bioequivalence occurs when two formulations of the
same compound have the same bioavailability and
the same rate of absorption
2-Distribution
 Distribution: Movement of drug from the central compartment (blood) to peripheral
compartments (tissues) where the drug is present.
 Distribution of a drug from systemic circulation to tissues is dependent on lipid solubility ,
ionization, molecular size , binding to plasma proteins , rate of blood flow and special
barriers
 The body compartments include extracellular (plasma, interstitial) and intracellular which
are separated by capillary wall and cell membrane
The major compartments are:
—plasma (5% of body weight)
—interstitial fluid (16%)
—intracellular fluid (35%)
—transcellular fluid (2%)
—fat (20%)
Cell membrane
Intracellular
compartment
Interstitial compartment
Extracellular
Endothelium of capillary wall
Intravascular (Plasma)
compartment
2-Distribution
 Selective distribution: Some drugs have special affinity for specific tissue. e.g. calcium in
bones, iodide in thyroid gland and tetracycline in bone and teeth.
Volume of Distribution:
The apparent volume of distribution, Vd, is defined as the volume of fluid required to
contain the total amount, Q, of drug in the body at the same concentration as that
present in the plasma, Cp.
 Vd is not a real volume, small volume indicates extensive plasma protein binding, but large volume indicates
extensive tissue binding.
 Vd is increased by increased tissue binding, decreased plasma binding and increased lipid solubility.
 N.B. in average 70 kg adult, the total body water is 42 liter, extracelllular volume is 12-14 liter and plasma
volume is 4 liter, so:
 -Drugs concentrated in plasma have Vd 3-4 L e.g. heparin.
 -Drugs distributed extracellularly have Vd 12-14 L e.g. aspirin.
 -Drugs distributed to all body fluids have Vd 42 L e.g. phenytoin and alcohol.
 -Drugs distributed intracellularly e.g. digoxin has Vd 500 L, imipramine 1600 L.
Drugs in vascular space
 Drugs are present in blood in :
1-Free form: active, diffusible, available for biotransformation and excretion.
2-Bound form (mainly to albumin): inert, non-diffusible, not available for metabolism and
excretion. It acts as a reservoir for drug.
Binding to plasma proteins is reversible
Significance of binding to plasma proteins:
* Two drugs may have affinity for plasma protein binding sites, thus compete with each
other leading to drug interactions.
* An example: Phenylbutazone and salicylates can displace warfarin (oral
anticoagulant) and oral hypoglycemics from plasma proteins.
* Drugs highly bound to plasma proteins are in general expected to persist in body
longer than those less bound and are expected to have lower therapeutic activity, less
efficient distribution and less available for dialysis in poisoning.
3-Biotransformation (Metabolism)
 The conversion of a substance from one form to another by the actions of
organisms or enzymes.
 Phases of biotransformation:
Phase I (Non-synthetic) reactions: introduction or unmasking of functional group by
oxidation, reduction or hydrolysis.
 These reactions may result in :
1-Drug inactivation (most of drugs)
2-Conversion of inactive drug into active metabolite (cortisone→ cortisol)
3- Conversion of active drug into active metabolite (phenacetin→ paracetamol)
4-Conversion to toxic metabolite (methanol → formaldehyde)
Phase II (Synthetic) reactions: Functional group or metabolite formed by phase I is
masked by conjugation with natural endogenous constituent as glucuronic acid,
glutathione, sulphate, acetic acid, glycine or methyl group.
 These reactions usually result in drug inactivation with few exceptions e.g. morphine-6conjugate is active
 Most of drugs pass through phase I only or phase II only or phase I then phase II.
 Some drugs as isoniazid passes first through phase II then phase I (acetylated then
hydrolyzed to isonicotinic acid).
First-pass metabolism
Prodrug  Active drug
or
Active drug  Inactive metabolite
or
Lipid soluble drug  Water soluble drug
3-Biotransformation (Metabolism)
 Sites of biotransformation and types of enzymes
1- Microsomal enzymes: they are present in smooth endoplasmic reticulum of cells especially
liver
 Microsomal enzymes catalyze:
-Glucuronide conjugation.
-Oxidation by microsomal cytochrome P450 enzymes (CYP450)
-Hydroxylation.
-Dealkylation.
-Reduction.
-Hydrolysis.
 They are affected by drugs and age
2- Non-microsomal enzymes: present in liver, kidney, plasma, skin and GIT…etc
 They catalyze:
-Conjugations rather than glucuronic acid.
-Oxidation by soluble enzymes in cytosol or mitochondria of cells e.g. MAO (monoamine
oxidase) and alcohol dehydrogenase.
-Reduction.
-Hydrolysis.
 Their activity is stable throughout life.
3-Biotransformation (Metabolism)
 Factors affecting drug metabolism
1-Drugs: They can stimulate (induce) or inhibit microsomal metabolizing enzymes.
* Enzyme induction: Some drugs increase the synthesis or decrease degradation of
enzymes.
 Examples: phenobarbitone, phenytoin, carbamazepine, rifampicin, griseofulvin,
testesterone, some glucocorticoids, tobacco smoking, ethyl alcohol (chronic).
 Importance of enzyme induction:
a) It decreases effect of other drugs.
b) Tolerance is sometimes explained by a drug inducing its own metabolism, e.g. ethyl alcohol,
phenobarbitone.
c) It is a mechanism of adaptation to environmental pollutants (pollutants induce their own
metabolism reducing their toxic effects).
* Enzyme inhibition (drugs that inhibit drug metabolism): it occurs faster than enzyme
induction and causes serious drug interactions.
 Examples: cimetidine, chloramphenicol, erythromycin, oestrogen, progesterone, sodium
valproate, cotrimoxazole, isoniazid, MAOIs, ketoconazole and ciprofloxacin
3-Biotransformation (Metabolism)
2-Genetics variation: The most important factor is genetically determined polymorphisms.
Example: Isoniazid is metabolized in the liver via acetylation. There are two forms (slow
and fast) of the enzyme responsible for acetylation (N-acetyl transferase ), thus some
patients metabolize the drug quicker than others. Slow acetylators are prone to
peripheral neuritis while fast acetylators are prone to hepatic toxicity.
3-Nutritional state: Conjugating agents are sensitive to body nutrient level. For example,
low protein diet can decrease glycine.
4-Dosage: High dose can saturate metabolic enzyme leading to drug accumulation. If
metabolic pathway is saturated due to high dose or depletion of endogenous conjugate,
an alternative pathway may appear e.g. paracetamol may undergo N-hydroxylation to
hepatotoxic metabolite.
5-Age: Drug metabolism is reduced in extremes of age (old patients and infants).
6-Gender: androgen, estrogen and glucocorticoids can affect CYP450 enzyme. Diazepam,
caffeine and paracetamol metabolism is faster in women while propranolol and lidocaine
metabolism is faster in men.
3-Biotransformation (Metabolism)
7-Disease state:
-Liver disease decreases the ability to metabolize drugs.
-In cases of heart failure and shock reduced hepatic flow will increase the effect of
rapidly metabolized drugs whose hepatic clearance is blood flow dependent e.g.
lidocaine, morphine, propranolol, verapamil….
-Kidney disease reduces the excretion of drugs.
8-Circadian rhythm. In rats and mice, the rate of hepatic metabolism of some drugs
follows a diurnal rhythm. This may be true in humans as well.
9-Route of administration: 1st pass effect occurs for drugs administered orally
4- Excretion of drugs
 It is the process by which a drug or metabolite is eliminated from the body
 Routes of excretion
1- Renal Excretion: It is the result of three processes:
Passive glomerular filtration, active tubular secretion in proximal tubules and passive
tubular re-absorption.
 Factors affecting renal excretion:
1-Glomerular filtration rate. Only free unbound water soluble drugs with low
molecular weight are filtered.
2-Change in urinary pH affect excretion of weak acid and base drugs. Thus:
-Alkalinization of urine by NaHCO3 increases excretion of acidic drugs e.g.
aspirin.
-Acidification of urine by NH4CL or vitamin C increases excretion of base drugs
e.g., amphetamine.
3-Active tubular secretion e.g., probenecid, penicillin, uric acid …...
4- Excretion of drugs
2-Gastrointestinal Tract:
a. Salivary glands: e.g., iodides, rifampicin and acidic drugs as salicylates.
b. Stomach: e.g., morphine (free and conjugated).
c. Large intestine: e.g., tetracycline, streptomycin.
d. Liver through bile, e.g.
-Ampicillin and rifampicin are excreted in active form so can be used in biliary
infection and ampicillin in typhoid carriers.
3-Sweat: e.g., rifampicin, vitamin B1.
4-Lungs: e.g., gases and volatile anesthetics.
5-Milk: basic drugs are trapped and excreted in acidic milk, e.g., morphine,
amphetamine.
Also chloramphenicol and oral anticoagulants can be excreted in milk.