Seminar on pharmacokinetics

SEMINAR ON
PHARMACOKINETIC
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Department of Pharmacology BVVS COP BGK

Pharmacokinetic (Greek:- pharmakon means ‘drug’ and kinetikos means
‘movement’).
“What does the BODY does to the DRUG” simple interchanged the BODY
and DRUG to make a definition. And as per the definition our body responds to
any drug by giving ADME effects.
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Absorption:- Absorption is a one of the most important phenomenon done by
body with response for drug.
ABSORPTION
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Factors affecting absorption are
Aqueous solubility:- Drugs given in solid from must dissolve in the aqueous biophase
before they are absorbed. For poorly water soluble drugs (aspirin, griseofulvin) rate of
dissolution governs rate of absorption. Ketoconazole dissolves at low pH; gastric acid is
needed for its absorption. Drug given as watery solution is absorbed faster then when the
same is given in solid form or as oily solution.
Concentration:- Passive diffusion depends on concentration gradient; drug given as
concentrated solution is absorbed faster then from dilute solution.
Area of absorbing surface:- Larger is the surface area, faster is the absorption.
Vascularity of the absorbing surface:- Blood circulation removes the drug from the site of
absorption and maintains the concentration gradient across the absorbing surface increased
blood flow and drug absorption.
Route of administration:- This effects drug absorption because each route as its own
peculiarities.
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Oral:- The effective barrier to orally administered drugs is the epithelial lining of
gastrointestinal tract which is lipoidal. Non-ionized lipid soluble drugs, eg : ethanol are
readily absorbed from stomach as well as intestine at rates proportional to there lipid: water
partition coefficient.
Acidic drugs eg: salicylates, barbiturates etc…
Basic drugs eg: morphine, quinine, etc…
Subcutaneous and Intramuscular:- By these routes the drug is deposited directly in the
vascular of the capillaries. Lipid soluble drugs passes readily across the whole surface of the
capillary endothelium. Capillaries having large par-cellular spaces do not obstruct absorption
of even large lipid insoluble molecules or ions.
Many drugs are absorbed in parenterally, s.c site is slower then that from i.m. site, but both
are generally faster and more consistent then oral absorption. eg: benzathine penicillin,
protamine zinc insulin, et…
Topical sites (skin, cornea, mucous membranes):- Systemic absorption after topical
application depends primarily on lipid solubility of drugs. However, only few drugs
significantly penetrate intact skin. Hyoscine, Fentanyl, GTN, Nicotine, Testosterone and
Estradiol have been used in this manner. Eg: Tannic acid applied over burnt skin as produced
hepatic necrosis, Timolal eye drops may produce bradycardia and precipitate asthma.
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Transport Process Across Cell Membrane
Transport of drug from small intestine to the systemic circulation takes place
by many methods like.
1. Passive Diffusion
Does not need energy for the
movement till equilibrium achieved.
Drugs diffuse across a cell membrane
from a region of high concentration (GI
fluids) to one of low concentration
(blood).
Diffusion rate is directly proportional
to the gradient but also depends on the
molecule’s lipid solubility, size, degree
of ionization, and the area of absorptive
surface. 6

The ionization of a weak acid HA is given by the equation:
(A-)
pH = pKa + log (HA) ……(1)
pKa is the negative logarithm of acidic dissociation constant of the weak
electrolyte. If the concentration of ionized drug (A-) is equal to concentration
of unionized drug (HA),then
(A-)
(HA) = 1
Since log 1 is 0 ,under this condition
pH = pKa …..(2)
Thus, pKa is numerically equal to the pH at which the drug is 50% ionized.
If pH is increased by 1 scale, then
log (A-)/(HA) = 1 or (A-)/(HA) = 10 7

Similarly, if pH is reduced by 1 scale ,then
(A-)/(HA) = 1/10
Thus weakly acidic drug, which form salts with cations,
eg: sod. phenobarbitone, sod. Sulfadiazine, pot. penicillin-V, etc…
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Specialized transport
This can be carrier mediated or by pinocytosis.
Carrier mediated transport:- All cell membrane express a host of
transmembrane proteins which serve as carriers or transporters for
physiologically important ion, nutrients, metabolites, transmitters, etc…
Carrier transport is two types:
1) Facilitated diffusion:- The transporter belonging to the super-family of
solute carrier (SLC) transporters, operates passively without needing energy
and translocates the substrate in the direction of its electrochemical gradient,
i.e. from higher to lower concentration (Fig. A).
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2) Active Transport
• Need energy.
• Molecules move from low concentration to high concentration.
• Active transport seems to be limited to drugs structurally similar to
endogenous substances like- ions, vitamins, sugars, amino acids.
• These drugs are usually absorbed from specific sites in the small intestine.
 Active transport can be primary or secondary depending on the source of
the driving force.
i. Primary active transport (Fig. B).
ii. Secondary active transport In this type of active transport effected by another
set of SLC transporters, the energy pump one solute is derived from the
downhill movement of another solute (mostly Na+).
Symport & Antiport (Fig.C&D)
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 Endocytosis and Exocytosis
Process of engulfing either Pinocytosis or Phagocytosis. In Pinocytosis, fluid or
particles are engulfed by a cell. The cell membrane invigilates, encloses the
fluid or particles, then fuses again, forming a vesicle that later detaches and
moves to the cell interior. Energy expenditure is required. Pinocytosis probably
plays a small role in drug transport, except for protein drugs.
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DISTRIBUTION
 Distribution:- Drug distribution can be defined as the movement of drug
between blood and extra vascular tissues.
Distribution is very important to achieve the homeostasis between all body
compartments.
 When drug is administered into body and it reached into blood vessels, its
distribution starts as per the concentration gradient.
 The extent of drug distribution is depends on lipid solubility, ionization and
physiological pH.
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Factors:-
Greater Brain, liver, kidney.
1) Blood flow
Lower Skeletal muscle, adipose tissue.
2) Capillary permeability depends on
i. Capillary structure
ii. Chemical nature of drug
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3) Plasma protein binding Drug Plasma protein Big size
Acidic drug Albumin
Basic drug alpha acid glycoprotein
eg :- Highly plasma protein bound drug. - Warfarin, Diazepam - Tolbutamide,
phenytoin
4) Lipophilicity (lipid solubility) Lipid soluble drug can easily cross membrane.
5) Redistribution
muscle tissue
Tablet Brain/heart/kidney redistribution
fatty tissue perfused
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 Volume of distribution:- Apparent volume of distribution is defined as the
volume that would accommodate all the drugs in the body, if the concentration
was the same as in plasma
Expressed as: in Liters
Vd = Dose administered IV
Plasma concentration
Chloroquin – 13000 liters,
 Digoxine – 420 L, Morphine – 250 L,
Propranolol – 280 L,
Streptomycin and Gentamicin – 18 L,
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METABOLISM
Biotransformation is made up of two common terms- Bio- in living organism and
transformation- conversion of anything here drug from one form to another form,
which is required by the body.
Drug (lipid soluble) Biotransformation Polar (water soluble) Kidney Eliminate
The primary site for drug metabolism is liver, other are kidney, intestine, lungs
and plasma.
Biotransformation of drug many give any of this activity-
1. Inactivation of drugs eg :- Paracetamol, Propranolol.
2. Active metabolites from active drugs eg:-Codeine-morphine
Digitoxin-Digoxin
3. Activation of inactive drugs:-(Prodrug) more active stable
eg:-Levodopa-Dopamine
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OXIDATION
 This reaction involves addition of oxygen or –ve charged radical to drug or
Removal of hydrogen or +ve charged radical.
 Various oxidation reaction are oxygenation or hydroxylation of C-,N-, or
S-atoms; N or O-dealkylation.
eg: Barbiturates, Phenothiazines, Paracetamol and steroids.
 Microsomal drug oxidation requires Cytochrome P-450, Cytochrome P-450
reductase, NADPH and oxygen Steps are.
 Oxidised Cytochrome P-450 (Fe3+) combined with drug to form drug
Cytochrome P-450(Fe3+) complex.
BIOTRANSFORMATION REACTION
Non Synthetic
Phase-I/Functionalization Reaction
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 The reduced ‘Drug-Cytochrome P-450(Fe2+)” complex then combine with oxygen to form
‘Drug-Cytochrome P-450 (Fe2+)-O2’ complex.
This complex, in turn transfers one activated oxygen to the drug to form oxidized drug
metabolites and the other to hydrogen to form water. The ‘Cytochrome P-450(Fe3+) enzyme is
thus regenerated and is ready for reuse.
 NADPH donates an electron (e-) to the oxidised flavoprotein to from reduced flavoprotein
(Cytochrome P-450 reductase) which in turn reduces the ‘Drug-Cytochrome P-450(Fe3+)’
complex to Drug-Cytochrome P-450(Fe3+) (to complete the chain, the latter is reduced at the
cost of NADPH which is oxidized to NADPH⁺).
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REDUCTION:- This reaction converse of oxidation and involve Cytochrome
P-450 enzyme working in the opposite direction. Alcohols, Aldehydes, quinines,
are reduced. E.g.:- Chloral hydrate, Chloramphenicol, Levodopa, Halothane and
Warfarin.
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HYDROLYSIS:- This is cleavage of drug molecule by taking up water molecule
of water. Similarly amides and polypeptides are hydrolyzed by amidase and
peptidases. Hydrolysis occurs in liver, intestines, plasma and other tissues.
Ex: Choline esters, Procaine, Lidocaine, Pethidine, oxytocine.
Ester+H2O esterase Acid+ Alcohol
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CRYSTALLIZATION:- This is a formation of ring structure from a straight
chain compound, e.g..- Proguanil.
DECYCLIZATION:- This is opening of ring structure of cyclic drug molecule
like Barbiturate, Phenytoin.
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Synthetic
Phase-II/Conjugation Reaction
GLUCURONIDE CONJUGATION:- Parent drug or their phase-1
metabolites that contain phenolic, alcoholic, carboxylic, amino or mercapto
groups can undergo conjugation reaction with Uridine diphosphate glucuronic
acid (UDPGA) catalysed by microsomal UDP–glucuronyl transferase enzymes to
yield dug-glucuronide conjugates which are polar, Readily excreted and often
inactive.
Example- Chloramphenicol, Aspirin,
paracetamol, Lorazepam, morphine,
Metronidazole.
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ACETYLATION
Compound having amino or hydrazine, residue are conjugated with the help of
acetyl coenzyme A.
Example:- Sulfonamide, Ionized, Dapsone, PAS, Histamine etc.
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METHYLATION
 The amine and phenols can be Methylated. Methionine and Cysteine act as a
methyl donor.
Example:- Adrenaline, Histamine, Nicotinic acid, Methyldopa, Captopril.
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SULPHATE CONJUGATION
This reaction is catalyzed by a family of enzymes called sulfotransferases that are
present in the cell cytoplasm of varies organs.
The essential cofactor (sulfate donor) for this enzyme is 3 phoshoadenosin-5-
phosphosulfate (PAPS). Sulfate conjugates being highly polar compounds are
readily excreted in the urine. Many phenolic, alcoholic and aromatic amine drugs
undergo sulfate conjugation and these include Aspirin, Methyldopa, Paracetamol,
Hydroxy–coumarines, Corticosteroids and Chloramphenicol.
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Amino acid Conjugation ( in mitochodria):- Acetylcoenyme–A derivation
of carboxylic acid drugs (eg: aspirin, benzoic acid, nicotinic acid and dexycholic
acid) can couple with glycine or glutamine in presence of Acetyl Coenyme
A–glyciae transferees enzymes in mitochondria but it is a minor metabolic
pathway.
Glutathione conjugation:- This is carried out by glutathione–S-transferase
(GST) forming a Mercapturate. It is normally a minor pathway. However, it
serves to inactivate highly reactive quinine or epoxide intermediates formed
during metabolism of certain drugs. eg: Paracetmol
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Ribonucleotide /nucleotide synthesis
This pathway is important for the activation of many purine’s and
pyrimidine’s anti-metabolites used in cancer chemotherapy.
Most drugs are metabolized by many pathways, simultaneously or
sequentially as illustrated.
Rates of reaction by different pathway often very considerably. A variety
metabolites (some more some less) of a drug may be produced. Stereoisomer's
of a drug may be metabolized differently and at different rates, eg: S-warfarin
rapidly undergoes ring oxidation, while R-warfarin is slowly degraded by side
chain reduction.
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Elimination:- It is defined as the removing waste material in the body.
Excretion or Elimination
URINE:- Through the kidney. It is most important channel of excretion for
most of drugs.
FACES:- Apart form the unabsorbed fraction, most of the drug present in faces
is derived from bile. Most of the drug, including that released by deconjucation
of glucuronides by bacteria in intestines is reabsorbed and ultimately excretion
occurs in urine. Examples:- Erythromycin, Ampicilllin, Rifampin, Tetracycline,
Oral contraceptives, Phenolphthalein.
MILK:- The excretion of drug in milk is not important for the mother, but the
sucking infant inadvertently receives the drug.
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EXHALED AIR:- Gases and volatile liquids (general anesthetics, paraldehyde,
alcohol) are eliminated by lungs, irrespective of their lipid solubility. Alveolar
transfer of the gas/vapour depends on its partial pressure in the blood. Lungs also
serve to trap and extrude any particulate, matter injected i.v.
SALIVA AND SWEAT:- These are of minor importance for drug excretion.
Lithium, potassium iodide, thiocynate, rifampin and heavy metals are present in these
secretions.
RENAL EXCREATION:- The kidney responsible for excreting all water soluble
substances. The amount of drug or its metabolites ultimately present in urine is the
sum total of glomerular filtration, tubular re-absorption and tubular secretion.
GLOMERULAR FILTRATION:- Glomerular capillaries have pores larger than
usual; all non-protein bound drug (whether lipid-soluble or insoluble) presented to the
glomerulus is filtered. Thus, glomerular filtration of a drug depends on its plasma
protein binding and renal blood flow. Glomerular filtration rate (g.f.r.),
normally-120 ml/min, declines progressively after the age of 50, and is low in renal
failure.
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TUBULAR REABSORPTION:- This occurs by passive diffusion and depends
on lipid solubility and ionization of the drug at the existing urinary pH. Lipid-
soluble drugs filtered at the glomerulus back diffuse in the tubules because
99%, of glomerular filtrate is reabsorbed, but non-lipidsoluble and highly
ionized drugs are unable to do so. Thus, rate of excretion of such drugs,
e.g. aminoglycoside antibiotics.
This principle is utilized for facilitating elimination of the
drug in poisoning, i.e. urine is alkalinized in barbiturate and salicylate
poisoning. Though elimination of weak bases (morphine, amphetamine) can be
enhanced by acidifying urine, this is not practiced clinically, because acidosis
can induce rhabdomyolysis, cardio-toxicity and actually worsen outcome. The
effect of changes in urinary pH on drug excretion is greatest for those having
pKa values between 5 to 8, because only in their case pH dependent passive
re-absorption is significant.
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TUBULAR SECRETION:- This is the active transfer of organic acids and
bases by two separate classes of relatively nonspecific transporters (OAT and
OCT) which operate in the proximal tubules. If renal clearance of a drug is
greater than 120ml/min (g.f.t.), additional tubular secretion can be assumed to
be occurring. Active transport of the drug across tubules reduces concentration
of its free form in the tubular vessels and promotes dissociation of protein
bound drug, which again is secreted.
(a) Organic acid transport (through OATP ) for penicillin, probenecid, uric acid,
salicylates, indomethacin, sulfinpyrazone, nitrofurantoin, methotrexate, drug
glucuronides and sulfates etc.
(b) Organic base transport (through OCT) for thiazides, amiloride, triamterene,
furosemide, quinine, procainamide, choline, cimetidine, etc.
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Many drug interactions occur due to competition for tubular secretion
e.g. (i) Salicylates block uricosuric action of probenecid and sulfinpyrazone
and decrease tubular secretion of methotrexate.
(ii) Probenecid decreases the concentration of nitrofurantoin in urine, increases
the duration of action of penicillin/ampicillin and impairs secretion of
methotrexate.
(iii)Sulfinpyrazone inhibits excretion of tolbutamide.
(iv)Quinidine decreases renal and biliary clearance of digoxin by inhibiting
efflux carrier P-gp. Tubular transport mechanisms are not well developed at
birth. As a result, duration of action of many drugs, e.g. penicillin,
cephalosporins, aspirin is longer in neonates. These systems mature during
infancy. Renal function again progressively declines after the age of 50 years;
renal clearance of most drugs is substantially lower in the elderly (>75 yr).
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THANK U
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Seminar on pharmacokinetics

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