Biotransformation and Elimination of Drugs
I.
Biotransformation
A.
Metabolic processes, in general, have the overall effect of converting
drug molecules into more polar compounds.
B.
In general, the effect of this should be to decrease tubular
re-absorption in the kidney and thus increase drug elimination.
C.
Generally, it also means an immediate loss of pharmacological activity
because transport into the site of action is hindered (less lipid soluble) or
the molecule no longer fits into the receptor site.
D.
There are exceptions however, and a number of `new' drugs have been
discovered as active metabolites.
E.
Metabolism takes place by enzymatic catalysis.
F.
Most metabolism occurs in the liver although other sites have been
described, such as intestinal wall, kidney, skin, blood.
G.
There are four main patterns of drug metabolism.
1.
oxidation - Oxidation is the addition of oxygen and/or the removal of
hydrogen. Most oxidation steps occur in the endoplasmic reticulum.
2.
reduction - Add a hydrogen or remove oxygen
3.
hydrolysis - Addition of water with breakdown of molecule. In blood
plasma (esterases) and liver
4.
conjugation - Conjugation reactions involve the addition of molecules
naturally present in the body to the drug molecule. The drug may have undergone
a phase I reaction.
H.
Induction - A large number of drugs can cause an increase over time in
liver enzyme activity.
I.
Inhibition - Alternately some drugs can inhibit the metabolism of other
drugs.
II.
Elimination of Drugs
A.
The major routes of elimination include:
1.
renal
2.
biliary - The liver secretes 0.25 to 1 liter of bile each day. Some drugs
and their metabolites are excreted by the liver into bile.
3.
pulmonary - The lung is the major organ of excretion for gaseous and
volatile substances. The breathalyzer test is based on a quantitative pulmonary
excretion of ethanol. Most of the gaseous anesthetics are extensively eliminated
in expired air.
4.
salivary - This is not really a method of drug excretion as the drug will
usually be swallowed and reabsorbed, thus a form of 'salivary recycling'. Drug
excretion into saliva appears to be dependent on pH partition and protein
binding.
B.
The major organ for the excretion of drugs is the KIDNEY.
1.
The functional unit of the kidney is the nephron in which there are three
major processes to consider
a.
Glomerular filtration - Most drugs are readily filtered from the blood
unless they are tightly bound to large molecules such as plasma protein or have
been incorporated into red blood cells.
b.
Tubular secretion - Drugs or compounds which are extensively secreted,
such as p-aminohippuric acid (PAH), may have clearance values approaching
the renal plasma flow rate of 425 to 650 ml/min, and are used clinically to
measure this physiological parameter
c.
Tubular re-absorption - Drugs which are present in the glomerular
filtrate can be reabsorbed in the tubules. The membrane is readily permeable to
lipids so filtered lipid soluble substances are extensively reabsorbed. Thus if
a drug is non-ionized or in the unionized form it maybe readily reabsorbed.
2.
Renal Clearance
a.
One method of quantitatively describing the renal excretion of drugs is
by means of the renal clearance value for the drug.
b.
Calculated as part of the total body clearance for a particular drug.
c.
Renal clearance can be used to investigate the mechanism of drug
excretion.
d.
If the drug is filtered but not secreted or reabsorbed the renal
clearance will be about 120 ml/min in normal subjects.
e.
If the renal clearance is less than 120 ml/min then we can assume that at
least two processes are in operation, glomerular filtration and tubular
re-absorption.
f.
If the renal clearance is greater than 120 ml/min then tubular secretion
must be contributing to the elimination process.
g.
It is also possible that all three processes are occurring
simultaneously.