Amity Institute of Biotechnology
AMITY UNIVERSITY UTTAR PRADESH,
SAAD SABIR SIDDIQUI
semester (Batch: 2014-18)
Mr. Rajnish Kumar
Amity Institute of
is currently defined as the study of drug absorption, distribution,
metabolism, and excretion. Clinical pharmacokinetics is
the utilization of pharmacokinetic standards to the safe administration of
medications in patient’s. Primary objectives of clinical pharmacokinetics
incorporate upgrading viability and diminishing toxicity of a patient’s treatment.
The improvement of solid connections between tranquilize fixations and their
pharmacologic reactions has empowered clinicians to apply pharmacokinetic
standards to genuine patient circumstances. The basic procedures which is associated
with pharmacokinetics are absorption, distribution, metabolism and excretion
and they are known by the acronym ‘ADME’.
Absorption is the process by which drugs passes
through before entering the systematic circulation(blood). Given by any route
other than intravenously, drug molecules must cross tissue membranes (e.g. skin
epithelium, subcutaneous tissue, gut endothelium, capillary wall) to enter the
the process in which there is dispersion of drug from one location to another within
the body through fluids or tissues. After entering the blood, drug molecules must cross
capillary walls to enter the tissues, reach cell membranes and enter cells.
Metabolism (Biotransformation) is the process by
which active drugs to inactive and oblique or inactive drugs to active and they
are chemically altered to make them sufficiently water-soluble for excretion in
urine or faeces (via the biliary tract). Metabolism occurs in a variety of body
organs and tissues, but chiefly in the skin, gut wall, liver and kidney.
Excretion is the process by which drugs exits the
body. The drugs that are lipid-soluble are modified to water-soluble
metabolites before they are excreted out via kidney or into the intestine via bile
and the drugs that are sufficiently water-soluble will be excreted unchanged in
the process by which drugs pass through various biological barriers and reaches
the systematic circulation(blood). Given by any route other than intravenously,
drug molecules must cross tissue membranes (e.g. skin epithelium, subcutaneous
tissue, gut endothelium, capillary wall) to enter the blood.
The movement of
the drug from the gastrointestinal tract, depending on their chemical
properties, drugs may be absorbed from the gastrointestinal tract by either by passive
diffusion or active transport.
diffusion: The drug moves from higher to lower concentration
(Fick’s low). Passive diffusion does not contain a provider(carrier). Most of
the drugs gain access to the body by this mechanism. Drugs that are lipid-soluble
easily pass through most of the membranes in the body due to their solubility
in the membrane bi-layers. Drugs which are water soluble penetrate the cell
membrane via pores or the aqueous channels that are present in the cell
membrane. Other agents can enter the cell via specialized transmembrane
provider(carrier) proteins that facilitate the passage of big molecules. This
system is known as facilitated diffusion.
transport: This mode of drug access involves particular provider(carrier)
proteins that pass the membrane. Active transport is energy-dependent and is driven
by the hydrolysis of adenosine tri-phosphate. It is capable of moving drugs
against a concentration gradient that is, from a region of lower to higher drug
exocytosis: This type of delivery transports drugs of
exceptionally large size across the cell membrane. Endocytosis involves
engulfment of a drug molecule by the cell membrane and transport into the cell
by pinching off the drug-filled vesicle. Exocytosis is the reverse of
endocytosis and is used by cells to secrete many substances by a similar
vesicle formation process.
Ø Plasma protein binding
system can transport generally insoluble substances. These substances are
exchanged by binding to the proteins which have an extremely amphipathic
structure. The groups that are hydrophilic renders the protein solubility in
water and the compounds that are lipophilic are pulled in to the lipophilic
groups and are loosely bound to the protein molecules. The majority of the
drugs go in the plasma are partly in solution and partly bound to the plasma
protein. The bound drug is inert and the unbound drug is dynamic. The
proportion of bound to the unbound drug fluctuates. Binding of the drug is
reversible. The acidic part of the drug binds to the albumin and the basic part
to ?1 – acid glycoprotein.
The drug binds
to form a dynamic equilibrium with the plasma protein, because of the plasma
protein the free dug reaches the receptor. This means that once the free drug
enters the target tissue then the protein bound drug will be released to
maintain equilibrium. On the off chance that two medications tie at a similar
site of the protein and are managed together at that point there can be issues.
e.g. Warfarin and aspirin, as aspirin dislodge warfarin from its bound protein
because of which there are raised levels of warfarin in the unbound state and this
can prompt warfarin toxicity.
Ø The role of the liver
in drug distribution
drug is absorbed by the gastrointestinal tract, it is taken up by the
constituent of the blood line stream called the hepatic portal system. Most of
the drugs are absorbed into this organization except for the lipid which are
absorbed into the lymphatic system and then delivered into the blood by the
thoracic duct into the superior vena cava. The hepatic portal system is
designed to take digested grocery into the liver where it can be processed, in
some cases it is stored before being distributed and it is possible that this
may happen to the drug and the drug would be metabolized before reaching the
rest of the physical structure. Such drugs that metabolized by the liver are
said to have a heights hepatic first base on balls. Hence drugs with a very
high hepatic first pass cannot be given orally.
Metabolism or Biotransformation
being excreted, the medicine is metabolised by the liver, kidney or other
sites. It refers to the process of making the drug more polar (more water-soluble), which may lead to medicine
inactivation and excretion.
may be more or less (prodrug) active than the parent medicine. The liver is
the major source of these enzymes (P450 enzymes), though they may be present in
the gastrointestinal tract, heart, lung, brain and kidney.
1. Phase I
I reactions (non-synthetic) involve minor structural modifications of the
parent structure via oxidation, reduction or hydrolysis to produce smaller,
more water-soluble metabolite. These are predominantly handled by enzymes known
as the Cytochrom P450 enzymes.
I reactions frequently provide a ‘handle’ for further modifications by
subsequent Phase II reactions.
2. Phase II
II reactions (synthetic) involve the coupling of a water-soluble endogenous
molecule such as glucuronic acid, sulphate, glutathione to a chemical (parent
compound and/or Phase I metabolite) to facilitate excretion.
most common causes of medicine-to-medicine interactions are
pharmacokinetics, particularly metabolic ones. These are known as the cytochrome P450
large number of clinically important interactions arise from inhibition or induction of
substrates (medicines that are significantly metabolised by the
Inhibitors are compounds
that are generally capable of inhibiting the metabolism of the various
substrates. As a result, administration of the inhibitor may lead to an
increased plasma concentration of the substrate. For example,
ciprofloxacin inhibits the CYP3A4 enzyme that metabolises clozapine which
may lead to a toxicity of clozapine.Inducers
of the specified P450 have the capacity to increase the activity of the
designated enzyme and therefore reduce the plasma concentrations of the
listed substrates. For example, carbamazepine induces the metabolism of
cyclosporin via the CYP3A4 enzyme, leading to a reduction in plasma levels
of cyclosporin and hence loss of efficacy.
Excretion is the removal of the substance from the body.
Some drugs are either excreted out unchanged or some are excreted out as
metabolites in urine or bile. Drugs may also leave the body by natural routes
such as tears, sweat, breath and saliva. Patients with kidney or liver problem
can have elevated levels of drug in the system and it may be necessary to
monitor the dose of the drug appropriately since a high dose in the blood can
lead to drug toxicity.