Chemistry Reference
In-Depth Information
Metabolic pathways
Foreign compounds such as drugs taken into the body undergo enzymatic
transformations, which usually result in a loss of pharmacological activity.
This is known as
detoxification
. Occasionally, the action of these enzymes
may convert an inactive compound (for example, a prodrug) into a pharma-
cologically active compound. In this case, the process is described as
bioac-
tivation
. Prodrugs are pharmacologically inactive derivatives of the active
molecule that are designed to break down within the body to release the
active drug. The prodrug approach is often used in pharmacy to overcome
problems such as poor absorption, instability or toxicity when the parent
drug is given orally. Examples include anticancer agents such as cyclophos-
phamide or antibiotics such as pivmecillinam. The prodrug approach can
also be used if the parent drug has an unpalatable taste or smell that needs
to be disguised, as is the case in the disease nephropathic cystinosis, where
the only drug treatment for the condition, cysteamine, tastes and smells so
bad it affects patient compliance.
Biotransformations
There are two main types of biotransformation observed in the body, im-
aginatively called
Phase 1
and
Phase 2
reactions, although many drugs
undergo both types of process. Phase 1 reactions are reactions in which a
new functional group is introduced into the molecule, or an existing group
is converted into another (usually more water-soluble) derivative. Phase 2
reactions, or conjugations, are where an existing functional group in the
molecule is masked by the addition of a new group. The conjugate is
formed between the drug and a hydrophilic compound such as glucuronic
acid and the resulting conjugate (a glucuronide) will usually be much more
water soluble than the parent drug. Most drugs are hydrophobic and so not
inherently water soluble. Metabolism to a more water-soluble and less toxic
derivative terminates drug action and allows the body to excrete the drug
easily in the urine. If the administered drug is already hydrophilic, the
molecule is often excreted unchanged.
The processes involved in drug metabolism involve simple chemical
reactions such as oxidation (the most common), reduction and dealkylation
and are influenced by a number of factors including:
•
Genetic factors
. Differences are observed between species (important since most
medicines intended for human use are tested first in animals) and between indi-
viduals in a population. The science of
pharmacogenomics
has arisen to study
the influence of genetic variation on drug action in patients and to study how the
