Phase I metabolism may
either detoxify or toxify.
• Phase I reactions produce a more polar
molecule that is easier to eliminate.
• Phase I reactions can sometimes result
in a substance more toxic than the
originally ingested substance.
• An example is the Phase I metabolism
of acetonitrile
The Liver
• Oral administration frequently brings the
drugs (via the portal system) to the liver
Metabolism of Drugs (cont.)
• Phase II metabolism links the drug to still
more polar molecules to render them even
more easy to excrete
UDP Glucuronic Acid
Glucuronic Acid
HO
O
HO
O
O
P
O
P
O
O
O
NH
O
glucuronosyltransferase
enzyme
N
HO
OH
OH
O
Drug
O
HO
R
O
HO
HO
O
O
HO
OH
OH
OH
More easily excreted than ROH itself
R
OH
Drug
Metabolism of Drugs (cont.)
• Another Phase II reaction is sulfation
(shown below)
NH2
N
O
O
R
OH
S
O-
N
O
O
P
O
N
O
O-
SO3-
N
R
Drug
O
O
P
OH
O-
O-
3'-Phosphoadenosine-5'-phosphosulfate
O
Sulfated Drug
(more easily excreted)
Phase II Metabolism
• Phase II reactions most commonly
detoxify
• Phase II reactions usually occur at polar
sites, like COOH, OH, etc.
Manufacture of Drugs
•
•
•
•
Pharmaceutical companies must make a profit to continue to exist
Therefore, drugs must be sold at a profit
One must have readily available, inexpensive starting materials
One must have an efficient synthetic route to the compound
– As few steps as possible
– Inexpensive reagents
• The route must be suitable to the
“scale up” needed for the production of
at least tens of kilograms of final
product
• This may limit the structural complexity
and/or ultimate size (i.e. mw) of the
final product
• In some cases, it may be useful to
design microbial processes which
produce highly functional, advanced
intermediates. This type of process
usually is more efficient than trying to
prepare the same intermediate using
synthetic methodology.
Toxicity
• Toxicity standards are continually becoming
tougher
• Must use in vivo (i.e. animal) testing to screen for
toxicity
– Each animal is slightly different, with different metabolic
systems, etc.
– Thus a drug may be toxic to one species and not to
another
Example: Thalidomide
Thalidomide was developed by German pharmaceutical
company Grünenthal. It was sold from 1957 to 1961 in almost
50 countries under at least 40 names. Thalidomide was
chiefly sold and prescribed during the late 1950s and early
1960s to pregnant women, as an antiemetic to combat
morning sickness and as an aid to help them sleep. Before its
release, inadequate tests were performed to assess the drug's
safety, with catastrophic results for the children of women who
had taken thalidomide during their pregnancies.
Antiemetic = a medication that helps prevent
and control nausea and vomiting