Chemistry Reference
In-Depth Information
A number of oxygen-, nitrogen- and sulfur- containing drugs can
be metabolised by addition of a methyl group.
O
-Methylation and
N
-
methylation are the most common reactions and are catalysed by methyl-
transferase enzymes such as catechol
O
-methyltransferase (COMT), one of
the enzymes involved in terminating the action of adrenaline (epinephrine)
and noradrenaline (norepinephrine). As in the case of acetylation reactions
above, the
O
-methyl and
N
-methyl derivatives are more lipophilic and
less water soluble than the parent drug. This metabolic transformation
should also be viewed as a method of terminating pharmacological action
rather than as a means of increasing water solubility prior to excretion
by the kidneys.
N
-Methylation reactions are less common, although sero-
tonin, histamine and tyramine are examples of
endogenous hormones
metabolised by methylation of the nitrogen.
Stereochemistry
Drug metabolism may be influenced by stereochemical factors if the
molecule in question possesses one or more chiral centres. Examples of
drugs that show stereochemical differences in rates of metabolism include
a-methyldopa (where the (
S
) isomer is decarboxylated more rapidly than
the (
R
) isomer) and the enantiomers of warfarin, which are reduced at
different rates. The well-known endogenous compound mevalonic acid
(3,5-dihydroxy-3-methylpentanoic acid) is chiral and exists as two enantio-
mers. When a racemic mixture of mevalonic acid is fed to animals, one
optical isomer is absorbed and metabolised, while virtually all of the other
isomer is excreted by the kidneys into the urine.
The fact that different rates of metabolism are observed when chiral
drugs are used should not come as a surprise. Biotransformations are
carried out in the body by enzymes, such as CYP450. These enzymes are
themselves chiral since they are proteins and are composed of amino acids,
which are, with the exception of glycine, all chiral. A chiral enzyme will, in
general, interact differently with each enantiomer of a chiral drug. This
effect is so widespread as to be considered normal.
Almost all drug-macromolecule interactions occurring in the body
show chiral discrimination. This is true whether they are drug-enzyme or
drug-receptor in nature. The situation is complicated further because some
drugs show stereoselective absorption, distribution and excretion between
enantiomers and it is difficult to determine which effects are due solely to
metabolism and which are due to other biopharmaceutical factors.
