A Dictionary of Terms Used in Drug Metabolism

Reference: The Merck Manual of Diagnosis and Therapy

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.

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PRINCIPLES OF DRUG ACTION

Prediction of Relative Solubilityof Organic Medicinal Agents

Examination of the structure of the following drug structures indicates the presence of both lipophilic
(nonpolar) and hydrophilic (polar) groups and substituents in each structure. The relative solubility of
each of these drugs is a function of the contributions of each of the individual structural features of
these molecules. For example, the relative solubility of an OMA is the sum of the contributions of each
group and substituent to overall solubility.

A. Laboratory Estimation of Relative Solubility

The relative solubility of organic drug molecules is measured by determining the extent of their
distribution into an aqueous solvent (usually pH 7.4 buffer to mimic the physiological environment) and
a lipid solvent (usually n-octanol to mimic the physiologic lipid environment). These experiments
generate a value, P, known as the partition coefficient for each compound.

B. Estimation of Relative Solubility

1. Comparison of Drug Structural Features

Given 2 or more drug structures, one should be able to estimate the relative solubility of each. For
example, Drug #2 (above) is similar in structure to Drug #1 EXCEPT that Drug #2 contains two additional
structural features - a phenolic OH function and a 2o-OH alcohol function. Since OH functions are
considered to be hydrophilic structural features (they H-bond to solvent H2O molecules thereby
increasing solubility in this medium) it would be reasonable to assume that Drug #2 is more hydrophilic
than Drug #1 or, saying it another way, Drug #1 is more lipophilic than Drug #2.

2. Mathematical Estimation of Relative Solubility

Experimentation has shown that the relative solubility of drug structure can be estimated by summing
the solubility contributions of individual groups and substituents in a drug structure. Quantitative values
have been determined to express the various solubility contributions of the structural features of drugs.
These solubility contributions are expressed as hydrophilic (negative) and lipophilic (positive)
hydrophobic bonding constants.

A tabulation of some of these hydrophobic bonding constants is provided in Dr. Riley's slides on Drug
Absorption.

To calculate a log P for an OMA (i) the molecule is dissected into its various groups, functionalities and
substitutents, (ii) appropriate hydrophobic bonding constants are assigned and summed and (iii)
compounds with log Pcalc values greater than 0 are considered lipophilic molecules that will have
solubility of less than 3.3% in water) and those with log Pcalc values less than 0 are considered to be
hydrophilic compounds with higher H2O solubility.
T. N. Riley, Ph.D. 05/08/00

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