PHARMACOKINETIC PROCESSES (LADME System)
Schematic depiction of pharmacokinetic processes
LIBERATION
Release of active ingredient from any dosage form (except IV injection, per oral elixir, rectal enema, eye drops)
before absorption (disintegration). A drug must be present in the form of a true solution at the site of absorption to
be absorbed.
ABSORPTION
Absorption comprises the processes involved in transferring a drug from the site of administration to the systemic
circulation.
With the exception of intravenous (i.v.) or intra arterial administration, a drug needs to cross a cell barrier (e.g.,
gastrointestinal epithelium) before reaching the systemic circulation.
Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration
by any route.
For an intravenous route, bioavailability is assumed to be equal to 100% (F=1).
Despite good gastrointestinal absorption, some oral drugs appear in low concentration (low bioavailability) in the
systemic circulation because of high first pass effect or presystemic elimination and incomplete extent of absorption.
There are various factors that influence the absorption of orally administered drugs.
Incomplete bioavailability after s.c. or i.m. injection is less common, but may occur due to local binding of the drug.
The greater bioavailability of a drug produces a greater effect.
For absorption, distribution, and excretion, drugs must cross one or many cell membranes by various transport
processes.
DISTRIBUTION
Once a drug enters the blood stream it is distributed to other compartments is called distribution. A drug is
distributed to site of action, tissue storage, site of biotransformation & site of excretion.
In systemic circulation, many drugs bind with plasma proteins, particularly albumin for acidic drugs, a l acid
glycoprotein and β globulins for basic drugs.
The free form is pharmacologically active, diffusible and available for metabolism and excretion. The protein bound
form is inactive, and not available for metabolism and excretion.
Volume of distribution (Vd) depends on plasma protein binding, lipid solubility, ion traping of drug, blood flow to
tissue, membrane barriers and body weight.
METABOLISM OR BIOTRANSFORMATION
Biotransformation, or drug metabolism, is the enzyme-catalyzed conversion of drugs to their metabolites. Most drug
biotransformation takes place in the liver, but drug-metabolizing enzymes are found in many other tissues, including
the gut, kidneys, brain, lungs, and skin.
The cytochrome P450 enzyme family is the major catalyst of drug biotransformation reactions.
(Three main CYP gene families i.e. CYP1, CYP2 & CYP3, are involved in drug metabolism in human liver. Isoenzymes
CYP3A4 is responsible for metabolism of more than 50% of the drugs.)
The fundamental role of drug-metabolizing enzymes is to inactivate and detoxify drugs and other foreign compounds
(xenobiotics) that can harm the body.
Drug metabolites are usually more water soluble than is the parent molecule and, therefore, they are more readily
excreted by the kidneys. Some appeared as toxic metabolites.
Drug biotransformation reactions are classified as phase I functionalizations and phase II biosynthetic (conjugation)
reactions.
Phase I biotransformation includes oxidative, hydrolytic, and reductive reactions.
Phase II Biotransformation includes glucuronide conjugation, acetylation, sulfation, methylation, glycine
conjugation, glutathione conjugation, and water conjugation.
Factors modifying drug metabolism include genetics, the immaturity of drug metabolizing enzyme system (newborn,
especially premature), metabolic enzyme induction and inhibition, elderly, diseases, and drug-drug interaction,
hepatic blood flow, etc.
EXCRETION
Excretion is the removal of drug from body fluids and occurs primarily in the urine.
Other routes of excretion from the body include in bile, sweat, saliva, tears, feces, breast milk, and exhaled air.
Renal Drug Excretion
Most drugs are excreted in the urine, either as the parent compound or as a drug metabolite.
Drugs are handled by the kidneys in the same manner as are endogenous substances, undergoing processes of
glomerular filtration, active tubular secretion, and passive tubular reabsorption.
At the site of action, a drug binds with drug receptor and produces drug actions and effects.
Drug's activities are terminated mainly by biotransformation and or renal excretion.
