Absorption (Oral)
The transfer of compound across the intestinal lumen. The
intestinal vasculature feeds into the portal vein which
goes to the liver. Hence, total absorption does not mean
all compound will reach the systemic circulation (see
First Pass).
Absorption (General)
The transfer of compound across an external physiological
barrier. Compared to oral absorption, first pass
metabolism through the liver is avoided but extra-hepatic
first pass metabolism may occur.
AUC
Area Under the plasma (or blood) concentration versus
time Curve. Usually expressed for the time period
sampled, ie 5 min to 24 hours, or extrapolated from 0
time to infinity.
Biliary excretion
The excretion of compound related material may occur via
bile which flows from the liver to the duodenum via the
bile duct and gall bladder (note; rats do not have gall
bladders).
Bioavailability
Following extravascular administration, the percentage of
the dose that reaches the systemic circulation is called
the absolute or systemic bioavailability of a compound.
Bioequivalence
If given two products, one a standard and the other a
test formulation, the same maximum peak concentration at
a similar time (tmax) and the same AUC is attainable then
the products are bioequivalent.
Blood-Brain Barrier
The presence of tight junctions between the endothelial
cells of the cerebral vasculature makes the brain
capillaries less permeable than other vasculature. This
gives rise to the concept of a barrier between the blood
within brain tissue and the blood of the general
circulation. Lipophilic drugs may be able to diffuse
across this barrier whereas most hydrophilic compounds
cannot. Specific transport systems exist to facilitate
the transport of nutrients, eg the glucose transport
system, and some drugs are actively transported into the
brain via carrier mediated transport.
Chronopharmacokinetics
A little used term which describes the study of
pharmacokinetics as related to time (of dose). It may
also relate pharmacokinetic drug parameters to circadian
rhythm (biological clock) or diurnal/nocturnal variation
(day/night cycle).
Clearance
Blood Clearance (Clb) or plasma clearance (Clp) is
defined as the volume of blood or plasma cleared of drug
in a unit time. It is related to the volume in which the
drug is dissolved and the rate at which it is eliminated.
Therefore it may be defined as the product of volume of
distribution and the elimination rate constant.
Creatinine Clearance
Used as a measure of renal function, it is the ratio of
creatinine excreted in urine to the concentration of
creatinine in plasma. It may be used as an approximate
measure of glomerular filtration rate (see renal
clearance).
Cytochrome P450
A group of mixed function monooxidases primarily
responsible for metabolising many xenobiotics.
Distribution
The transfer of compound from the site of administration
to the total systemic circulation and then to
extracellular and intracellular water and tissues is
called distribution. Drug distribution is usually a rapid
and reversible process.
Enterohepatic Recirculation
The process by which drug-related material excreted via
the bile into the small intestine may be reabsorbed
across the gut wall back into the systemic circulation.
Excretion
The removal of compounds from the body is excretion.
Drugs may be excreted, unchanged or as metabolites, in
urine via the kidneys or in faeces via the bile. Volatile
compounds are often excreted in expired air by the lungs.
Excretion via other body fluids such as saliva, sweat, or
sexual fluids is well documented.
Expression Systems
An in vitro method used for the study of
biotransformation. A specific drug metabolising enzyme
can be expressed in a simple cell (eg yeast or bacterial)
by means of molecular biology manipulations. This may
then facilitate an understanding of which enzyme(s) are
responsible for the biotransformation of the drug.
Extraction Ratio
The extraction ratio of a drug ranges from 0 to 1
depending upon how well the organ eliminates or extracts
the drug from the blood flowing through it. If active
processes are involved then extraction ratio may exceed
unity.
First Pass
Following absorption from the gastrointestinal tract
drugs travel directly to the liver where some are
extensively metabolised before reaching the systemic
circulation.
FMO
Flavin-containing monooxygenases that catalyse oxidation
at nucleophilic nitrogen, sulphur and phosphorus atoms.
Multiple forms of this enzyme have recently been
identified.
Genetic Polymorphism
The term defines monogenetic traits that exist in the
normal population in at least two phenotypes, for example
the ABO blood groups. In the context of pharmacokinetics,
genetic polymorphism of drug metabolising enzymes gives
rise to distinct subgroups in the population that differ
in their ability to perform a certain drug
biotransformation.
Half-life
The time for the concentration of drug in blood or plasma
to decline to half its original level
Hepatic Clearance
Under conditions whereby the liver is the sole organ of
drug elimination, plasma clearance may be defined as the
product of blood flow (Q) and extraction ratio (ER).
Hepatocytes
Parenchymal liver cells rich in drug metabolising
enzymes. As opposed to microsomes or other sub-cellular
fractions, isolated hepatocytes represent a more
sophisticated model of hepatic metabolism capable of both
phase I and phase II biotransformations.
Hybrid Rate Constants
These are pharmacokinetic parameters such as and that are
composite rate constants consisting of two or more micro
rate constants, for instance k12 and k21, depending upon
the mathematical pharmacokinetic model.
Induction
A wide range of structurally unrelated compounds can
stimulate the synthesis of new enzyme molecules,
particularly mixed function oxidases. This may lead to
increased metabolic deactivation and concurrent loss of
efficacy of either the compound itself or of
co-administered drugs depending on the enzymes involved.
The term autoinduction refers to when the compound
induces the drug metabolising enzymes involved in its own
biotransformation.
Inhibition
A wide range of structurally unrelated compounds can
inhibit the metabolism of other drugs. This may lead to
the impaired metabolism of co-administered drugs with
potentially deleterious side effects. The usual mechanism
is competition for the same substrate binding site
although interference with drug transport, depletion of
hepatic glycogen, and functional impairment of enzyme
activity by hepatotoxicity have also been reported.
Intrinsic Clearance
The theoretical unrestricted maximum clearance of unbound
drug by an eliminating organ
Liver Slices
A method using precision cut thin slices of liver with
which hepatic biotransformations may be studied in vitro.
In terms of tissue architecture they may be considered to
be a closer model of whole liver in comparison to
isolated hepatocytes and sub-cellular fractions. Capable
of both phase I and phase II metabolism.
Mean Residence Time
The MRT is an estimate of the average time a drug
molecule resides in the body and encompasses absorption,
distribution and elimination processes.
Microsomes
A subcellular fraction obtained via differential
centrifugation of liver homogenates comprised mainly of
contains fragments (vesicles) of the endoplasmic
reticulum, which include important drug metabolising
enzymes.
Pharmacodynamics
The study of the relationship between drug concentration
and effect.
Pharmacogenetics
The study of genetic factors which contribute to
pharmacokinetic variability in man (see Genetic
Polymorphism section.)
Pharmacokinetics
Derived from the Greek words pharmakon (drug) and kinesis
(motion, change of rate), pharmacokinetics is the study
of the movement of a drug within the body and the
processes affecting it. It is essentially the study of
drug concentration with time.
Phase 1 reactions
A collective term describing a range of
biotransformations that generally result in metabolites
with polar groups and includes oxidation, reduction,
hydrolysis and hydration as well as isomeration and other
miscellaneous reactions.
Phase II reactions
A collective term to describe enzymes that conjugate
small endogenous molecules such as glucuronic acid,
sulphate, acetate, glutathione, amino acids and others
with polar functional groups on compounds or their phase
1 metabolites.
Protein Binding
A reversible association of the drug to the proteins of
blood, or more usually plasma. Albumin binds a wide
variety of drugs but is particularly important for weak
acids and neutral compounds. With weak bases binding to 1
- acid glycoprotein assumes a greater importance. Binding
is normally due to ionic, Van der Waals, hydrogen and/or
hydrophobic bonds. Such binding should not be confused
with irreversible binding which is a drug clearance
process.
Renal Clearance
The elimination of parent drug into the urine via the
kidneys is defined as renal clearance. Three mechanisms
are involved; passive diffusion through the glomerulus
(glomerular filtration rate or GFR), active tubular
secretion and passive reabsorption.
Volume of Distribution
Not a real volume but a mathematical expression. There
are three "volumes of distribution" terms which
may be encountered in pharmacokinetic analyses. These are
the initial volume of distribution, Vi , the volume of
distribution based on area, Vdb, and the volume of
distribution at steady state, Vdss.