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.

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).

Following extravascular administration, the percentage of the dose that reaches the systemic circulation is called the absolute or systemic bioavailability of a compound.

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.

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).

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.

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.

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.

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.

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).

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.

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.

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.

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.

The study of the relationship between drug concentration and effect.

The study of genetic factors which contribute to pharmacokinetic variability in man (see Genetic Polymorphism section.)

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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