Pharmacokinetics

¨What the body does to the drug ¨ The Process

• The study of the disposition of a drug Absorption relies on
• The disposition of a drug includes the process of o Passage through membrane to reach the blood
ADME o Passive diffusion of lipid soluble species
o Absorption
o Distribution Types of transmembrane transport
o Metabolism Passive Transport (downhill movement)
o Excretion Elimination o According to the concentration gradient of the
o Toxicity permeating drug the direction of diffusion was
from higher concentration to lower concentration
Routes of Administration ▪ Small molecules: membrane pores
Parenteral: Injection, Topical, Respiratory ▪ Large molecules: lipid diffusion
Enteral: Rectal, Oral o Not requiring energy
o Having no saturation
Drug Delivery System o Having no carriers
o Tablets o Candy o Not resisting competitive inhibition
o Injections o Gum
syringe o Implants The drugs which are unionize, have low polarity and
o Cigarettes o Gas higher lipid solubility are easy to permeate
o Beverages o Creams membrane.
o Patches o Others The drugs which are ionized, high polarity and lower
o Suppositories lipid solubility are difficult to permeate membranes

Intravenous, Buccal or rectal administration are ways
to bypass the liver and avoid ¨first pass¨
First Pass Metabolism
Dose > Destroy in Gut > Not absorbed > Destroyed by
gut wall > Destroyed by liver > To systemic circulation
*Bioavailability: the fraction of the administered dose
reaching the systemic circulation
Determination of bioavailability
• A drug given by the intravenous route will have an
absolute bioavailability of 1 (F=1 or 100%
bioavailability)
• While drugs given by other routes usually have an
absolute bioavailability of less than one
• The absolute bioavailability is the area under
curve AUC non intravenous divided by AUC
intravenous
Absorption
• the process by which drug proceeds from the site
of administration to the site of measurement
(bloodstream) within the body
• Necessary for the production of a therapeutic
effect
• Most drugs undergo gastrointestinal absorption.
This is extent to which drug is absorbed from gut
lumen into portal circulation
• Exception: IV Drug Administration
1. Effect of the environment pH on drug transport
o Most of drugs are weak acids are weak bases.
o The ionization of drugs may markedly reduce
their ability to permeate membranes
o The degree of ionization of drugs is
determined by the surrounding pH and their
pKa
2. Determination of how much drug will be found on
either side of a membrane:
o the relationship of pKa and the ratio of acid
base concentration to pH is expressed by the
Henderson Hasselbach equation:
o This equation is useful in determining how
much drug will be found on either side of a
membrane that separates two compartments
that differ in pH for example, stomach (pH
1.5) and blood plasma (pH7.4)
o The lipid solubility of the non-ionized drug
directly determines its rate of equilibration
o Henderson Hasselbach equation:
Use of pH determination
Urinary pH trapping (ion trapping)
o Acidification of urine using ammonium chloride
(NH4Cl) increases excretion of basic drugs as
amphetamine
o Alkalinization of urine using sodium bicarbonate
(NaHCO3) increases excretion of acidic drugs as
aspirin
Other forms of passive transport
• Filtration:
o Water solubility
o Small molecular
• Facilitated transport:
o Transport from high concentration to low
concentration
o Not requiring energy
o Requiring carriers
▪ E.g. The absorption of vitamin B12 from
GI tract
▪ The transportation of glucose to the
intracellular membrane of red blood cells
Conditions which need active transport:
• Na,-K,-ATPase
• The transmitters where concentrated in the
vesicle
• The excretion and secretion of renal tract
• Active transport can concentrate drugs
inserting organ or tissue (the iodine pump)
Summary: methods of transmembrane transport
Diffusion
Bulk Flow
Endocytosis
Ion Pair
Facilitated Transport
Active Transport
Most drugs are absorbed and distributed by diffusion.
Types of Cell Membranes
• Cell Membranes: this barrier is permeable to
many drugs molecules but not to others,
depending on their lipid solubility. Small pores, 8
angstroms, permit small molecules such as
alcohol and water to pass through.
• Walls of Capillaries: Pores between the cells are
larger than most molecules, allowing them to pass
freely, without lipid solubility being a factor
Biological barriers
• Bound/ ionized drug cannot pass through the
BBB!
• Blood/Brain Barrier: This barrier provides a
protective environment for the brain. Speed of
transport across this barrier is limited by the lipid
solubility of the psychoactive molecule.
• Placental Barrier: This barrier separates two
distinct human beings but is very permeable to
lipid soluble drugs.
Blood brain barrier
• Disruption by osmotic means
• Use of endogenous transport system
• Blocking of active efflux transporters
• Intracerebral implantation
Distribution
• The movement of drugs from the blood to and
from the tissue
• All of the fluid in the body (referred to as the total
body water), in which a drug can be dissolved, can
be roughly divided into 3 compartments:
o Intravascular (blood plasma found within
blood vessels)
o Interstitial/tissue (fluid surrounding cells)
o Intracellular (fluid within cells, i.e. cytosol)
• The distribution of a drug into these
compartments is dictated by it’s physical and
chemical properties
Total body water
Vascular 3 liters 4% BW
Extravascular 9 liters 13% BW
Intracellular 28 liters 41% BW
Distribution
• Apparent volume of distribution ( Vd)=
Amount of drugs in body /plasma drug
concentration
• Close up the huddle volume of distribution for
some drugs: Drug Vd (L)
Cocaine 140
Clonazepam 210
Amitriptyline 1050
Amiodarone 5000
Volume of distribution
Plasma-3 liters
Blood- 5 liters
Extracellular fluid- 18 liters
Total body water-50 to 60 liters
Volume Of Distribution ,Clearance ,And Elimination
Rate Constant
Volume 100 Liters -Clearance 10 L/Hr
Clearance =volume of blood cleared of drug per unit
time
Important Concepts
• Vd is a theoretical volume and determines the
loading dose
• Clearance is a constant and determines the
maintenance dose
• CL= kVd
• CL and Vd are independent variables
• K is a dependent variable
Factors affecting drugs VD
• Blood flow : rate varies widely as function of
tissue
Muscle=slow
Organs= fast
• Capillary structure:
o Most capillaries are ¨leaky¨ and do not
impede diffusion of drugs
o Blood brain barrier formed by high level
of tight junctions between cells
o BBB is impermeable to most water
soluble drugs
Drugs > 200 Da with low Po/w values cannot possibly
cross membrane- require specialized protein based
transmembrane transport systems slower distribution
Drugs < thousand daltons with high Po/w values -
simply diffuse between the lipid molecules that make
up membranes, while anything larger requires
specialized transport
Elimination
• The irreversible removal of the parent drugs from
the body
elimination = excretion / drug metabolism
(biotransformation)
Excretion
• The main process that body eliminates
¨unwanted¨ substances
• Most common route- biliary or renal
• Other routes- lung (through inhalation), skin
(through perspiration)
• Lipophilic drugs may require several metabolism
steps before they are excreted
Renal Excretion
Filtration Absorption Secretion
Renal excretion
• Glomerular filtration
o Protein bound drugs are not filtered
• Tubular reabsorption
o Highly lipid-soluble lower polar unionized
drug easy to reabsorb
o High water- soluble high polar ionized
drug uneasy to reabsorb
• Active secretion in the renal tubules
o Changing pH of tubular lumen fluid, may
change absorption extent of drug in urine
• Acidic urine =
o Alkaline drugs eliminated
o Acid drugs reabsorbed
• Alkaline urine =
o Acid drugs eliminated
o Alkaline drugs reabsorbed
• Renal disease decrease clearance
o Affects drug dosage
Affect of urine pH on dissociation of drugs
• weak acid drug alkaline urine
dissociation large excretion accelerate
• week basic drug acid urine
dissociation large excretion fast
• weak acid drug acid urine
dissociation small excretion reduce
• weak basic drug alkaline urine
dissociation small excretion slow
Hepatic excretion
Drugs can be excreted in bile, especially when they
are conjugated with glucoronic acid
Biliary Excretion of Drugs
• Drugs that are excreted mainly in the bile have
molecular weight in excess of 500
• Drugs with molecular weights between 300 and
500 are excreted both in urine and bile
• For these drugs, a decrease in one excretory route
results in a compensatory increase in excretion
via the other route
• Compounds with molecular weight of less than
300 are excreted almost exclusively via the
kidneys into urine
ADME-Summary
Drug (release and dissolution)-Absorption->
Drug in systemic circulation-Elimination-> Excretion
and metabolism
^ Drug in tissues-> Pharmacologic effect