Pharmacokinetics- Membrane transport, absorption, distribution, metabolism and excretion of drugs .Enzyme induction, enzyme inhibition, kinetics of elimination

1. Pharmacokinetics
By
Prof. Saba Shaikh

2. Pharmacokinetics
➢Membrane transport
➢Absorption
➢Distribution
➢Metabolism
➢Excretion of drug
➢Enzyme induction
➢Enzyme inhibition
➢Kinetics of elimination

3. Pharmacokinetics
• Pharmacokinetics is the study of the absorption, distribution,
metabolism and excretion (ADME) of drugs, i.e. the movement of the
drugs into, within and out of the body

4. • All these processes involve passage of the drug molecules across
various barriers—like the intestinal epithelium, cell membrane, renal
filtering membrane, capillary barrier and so on.
• To cross these barriers the drug has to cross the cell membrane or
pass in-between the epithelial or endothelial cells.

5. Mechanisms of Transport of Drugs Across
Biological Membranes
➢Passivetransfer
• Simple diffusion
• Filtration
➢Carrier-mediatedtransport
• Active transport
• Facilitateddiffusion
➢Endocytosis

6. Passive Transfer
• The drug moves across a membrane without any need for energy.
• Simple diffusion: is the transfer of a drug across the membrane in the
direction of its concentration gradient. Lipid soluble drugs are transferred
across membranes by simple diffusion—after dissolving in the lipids of the
cell membrane.
• Filtration: is the passage of drugs through aqueous pores in the
membrane. Water soluble drugs with molecular size smaller than the
diameter of the pores cross the biological membranes by filtration.

7. Carrier-mediated transport
• Active transport: is the transfer of drugs against a concentration
gradient(Low to high) and needs energy. It is carried by a specific carrier
protein. e.g. levodopa, iron, amino acids.
• Facilitated diffusion: is a unique form of carrier transport which differs
from active transport in that it is not energy dependent and the movement
occurs in the direction of the concentration gradient (High to low). The
carrier facilitates diffusion and is highly specific for the substance, e.g.
uptake of glucoseby cells, vitaminB12 from intestines.

8. Endocytosis
• Endocytosis is the process where small droplets are engulfed by the cell.
Some proteins are taken up by this process (like pinocytosis in amoeba).
• This process is currently being tried for delivery of some anticancer drugs
to the tissues.
• The reverse process— exocytosis is responsible for secretion of many
substances from cells, e.g. neurotransmittersstored in nerve endings.

9. ABSORPTION
• Absorption is defined as the passage of the drug from the site of
administration into the circulation.
• For a drug to reach its site of action, it must pass through various
membranes depending on the route of administration.

10. Factor affecting absorption

11. First Pass Metabolism
• is the metabolism of a drug during its passage from the site of absorption to the
systemic circulation. It is also called presystemic metabolism or first pass effect and is
an important feature of oral route of administration. Drugs given orally may be
metabolized in the gut wall and in the liver before reaching the systemic circulation.
• measures to compensate first pass effect
— dose has to be increased for some drugs like propranolol
— route has to be changed for some others like hydrocortisone

12. • Bioavailability refers to the rate and extent of absorption of a drug
from a dosage form.
• Bioavailability is the fraction of the drug that reaches the systemic
circulation following administration by any route. Thus for a drug
given intravenously, the bioavailability is 100%. On IM/SC injection,
drugs are almost completely absorbed while by oral route,
bioavailability may be low due to incomplete absorption and first pass
metabolism.

13. • Bioequivalence :Comparison of bioavailability of different
formulations of the same drug is the study of bioequivalence. Often
oral formulations containing the same amount of a drug from
different manufacturers may result in different plasma
concentrations, i.e. there is no bioequivalence among them.

14. DISTRIBUTION
• After a drug reaches the systemic circulation, it gets distributed to other tissues.
• It should cross several barriers before reaching the site of action. Like absorption,
distribution also involves the same processes, i.e. filtration, diffusion and
specialized transport.
• Various factors determine the rate and extent of distribution, viz lipid solubility,
ionisation, blood flow and binding to plasma proteins and cellular proteins.
• Unionised lipid soluble drugs are widely distributed throughout the body.

15. • Plasma Protein Binding:
• On reaching the circulation most drugs bind to plasma proteins; acidic
drugs bind mainly albumin and basic drugs to alpha-acid glycoprotein.
• The free or unbound fraction of the drug is the only form available for
action, metabolism and excretion while the protein bound form
serves as a reservoir.

16. • Clinical Significanceof Plasma Protein Binding:
• 1. Only free fraction is available for action, metabolism and excretion. When
the free drug levels in the plasma fall, bound drug is released.
• 2. Protein binding serves as a store (reservoir) of the drug and the drug is
releasedwhen free drug levels fall.
• 3. Protein binding prolongs the duration of action of the drug.
• 5. Chronic renal failure and chronic liver disease result in hypoalbuminaemia
with reduced protein binding of drugs. Highly protein bound drugs should be
carefully usedin such patients.

17. Volume of Distribution (Vd)
• For the purpose of pharmacokinetic studies, body can be considered as a single compartment into
which drugs are distributed uniformly. Each drug actually follows its own pattern of distribution from
plasma to other body fluids and tissues.
• Apparent volume of distribution is defined as the volume necessary to accommodate the entire
amount of the drug administered, if the concentration throughout the body were equal to that in
plasma. It relates the amount of the drug in the body to the concentration of the drug in plasma. It is
calculated as
Vd= Amount of drug in the body/ Plasma concentration

18. BIOTRANSFORMATION (METABOLISM)
➢Biotransformation is the process of biochemical alteration of the drug in the body.
➢Body treats most drugs as foreign substances and tries to inactivate and eliminate
them by various biochemical reactions. These processes convert the drugs into more
polar, water-soluble compounds so that they are easily excreted through the
kidneys.
➢Some drugs may be excreted largely unchanged in the urine, e.g. frusemide,
atenolol.
➢Site : The most important organ of biotransformation is the liver. But drugs are also
metabolized by the kidney, gut, mucosa, lungs, blood and skin.

19. • The primary site for drug metabolism is liver; others are—kidney,
intestine, lungs and plasma. Biotransformation of drugs may lead to
the following:
1. Inactivation
2. Active metabolite from an active drug
3. Activation of inactive drug

20. • Biotransformation reactions can be classified into:
• (a) Nonsynthetic/Phase I/Functionalization reactions: a functional
group is generated or exposed— metabolite may be active or inactive.
• (b) Synthetic/Conjugation/ Phase II reactions: an endogenous radical
is conjugated to the drug— metabolite is mostly inactive; except few
drugs, e.g. glucuronide conjugate of morphine and sulfate conjugate
of minoxidil are active.

21. 1. Non-synthetic reactions
➢Oxidation: This reaction involves addition of oxygen/negatively
charged radical or removal of hydrogen/positively charged radical.
➢Reduction: This reaction is the converse of oxidation and involves
cytochrome P-450 enzymes working in the opposite direction.
Alcohols, aldehydes, quinones are reduced.

22. ➢Hydrolysis: This is cleavage of drug molecule by taking up a molecule
of water.
➢ Cyclization: This is formation of ring structure from a straight chain
compound, e.g. proguanil.
➢ Decyclization: This is opening up of ring structure of the cyclic drug
molecule, e.g. barbiturates, phenytoin. This is generally a minor
pathway.

23. 2. Synthetic reactions
➢These involve conjugation of the drug or its phase I metabolite with
an endogenous substrate, usually derived from carbohydrate or
amino acid, to form a polar highly ionized organic acid, which is easily
excreted in urine or bile.

24. • Glucuronide conjugation: This is the most important synthetic reaction carried out
by a group of UDP-glucuronosyl transferases (UGTs). Compounds with a hydroxyl or
carboxylic acid group are easily conjugated with glucuronic acid which is derived
from glucose.Examples are— chloramphenicol, aspirin etc.
• Acetylation: Compounds having amino or hydrazine residues are conjugated with
the help of acetyl coenzyme-A, e.g. sulfonamides.
• Methylation: The amines and phenols can be methylated by methyl transferases
(MT); methionine and cysteine acting as methyl donors, e.g. adrenaline.
• Sulfate conjugation: The phenolic compounds and steroids are sulfated by
sulfotransferases (SULTs), e.g. chloramphenicol

25. • Glycine conjugation: Salicylates, nicotinic acid and other drugs having
carboxylic acid group are conjugated with glycine, but this is not a major
pathway of metabolism.
• 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 quinone or epoxide intermediates
formed during metabolismof certain drugs, e.g. paracetamol.
• Ribonucleoside/nucleotide synthesis: This pathway is important for the
activation of many purine and pyrimidine antimetabolites used in cancer
chemotherapy.

26. Microsomal Enzyme
• These are located on smooth endoplasmic reticulum (a system of microtubules
inside the cell), primarily in liver, also in kidney, intestinal mucosa and lungs.
• The monooxygenases, cytochrome P450, UGTs, epoxide hydrolases, etc. are
microsomal enzymes.
• They catalyse most of the oxidations, reductions, hydrolysis and glucuronide
conjugation.
• Microsomal enzymes are inducible by drugs, diet and other agencies.

27. Non-microsomal enzymes
➢These are present in the cytoplasm and mitochondria of hepatic cells
as well as in other tissues including plasma.
➢The esterases, amidases, some flavoprotein oxidases and most
conjugases are nonmicrosomal.
➢Reactions catalysed are: Some oxidations and reductions, many
hydrolytic reactions.

28. Enzyme induction
• Microsomal enzymes are located in the microsomes that line the smooth endoplasmic reticulum of
the liver cells.
• The synthesis of these enzymes, mainly cytochrome P450 can be enhanced by certain drugs and
environmental pollutants.
• This is called enzyme induction and this process speeds up the biotransformation of the inducing
drug itself and other drugs metabolised by the microsomal enzymes, e.g. phenobarbitone,
rifampicin, alcohol, cigarette smoke, DDT, griseofulvin, carbamazepine and phenytoin are some
enzyme inducers.

29. Clinical relevance of microsomal enzyme induction:
1. Drug interactions
a. Therapeuticfailure
b. Toxicity
2. Toleranceto drugs may develop
3. Result in disease
4. Variable response
5. Therapeuticapplication of enzymeinduction

30. Enzyme Inhibition
• Some drugs inhibit cytochrome P450 enzyme activity. Drugs like
cimetidine and ketoconazole bind to cytochrome P450 and thus
competitively inhibit the metabolism of endogenous substances like
testosterone and other drugs given concurrently.
• Enzyme inhibition by drugs is the basis of several drug interactions.
• Chloramphenicol, erythromycin, ketoconazole, cimetidine, ciprofloxacin
and verapamil are some enzyme inhibitors

31. Factors that Influence Biotransformation
• Genetic variation
• Environmental pollutants
• Age
• Diseases

32. EXCRETION
• Renal Excretion
• Kidney is the most important organ of drug excretion.
• The three processes involved in the elimination of drugs through kidneys
are glomerular filtration, active tubular secretion and passive tubular
reabsorption.

33. • Faecal and Biliary Excretion
• Unabsorbed portion of the orally administered drugs are eliminated through the
faeces. Liver transfers acids, bases and unionised molecules into bile by specific
transport processes.
• Large water-soluble conjugates are excreted in the bile.
• Some drugs may get reabsorbed in the lower portion of the gut and are carried
back to the liver. Such recycling is called enterohepatic circulation and it prolongs
the duration of action of the drug; examples are chloramphenicol, tetracycline,
oral contraceptives and erythromycin.

34. • Pulmonary Excretion:
• The lungs are the main route of elimination for gases and volatile liquids
viz. general anaesthetics and alcohol.
• Other Routes of Excretion
• Small amounts of some drugs are eliminated through the sweat and
saliva. Excretion in saliva may result in a unique taste with some drugs
like phenytoin, clarithromycin; metallic taste with metronidazole,
metoclopramide and disulfiram.
• Drugs like iodide, rifampicin and heavy metals are excreted through
sweat.

35. CLINICAL PHARMACOKINETICS
• The knowledge of pharmacokinetics is clinically useful for several
purposes including selection and adjustment of the dosage regimen, and
to obtain optimum effects from a drug.
• The three most important pharmacokinetic parameters are bioavailability
, volume of distribution and clearance.

36. • Clearance (CL) is the volume of plasma freed completely of the drug in unit
time. It can be calculated by the ratio of the rate of elimination to the
plasma concentration.
• CL= Rate of elimination/ Plasma concentration
• Clearance is expressed as ml/litre/unit time.
• Clearance is the most important factor determining drug concentration
and should be considered when any drug is intended for long-term
administration.