Notes from Drug metabolism

1. Most of the chemicals we are exposed to on a day to day basis are not required for normal
biological function.
a. May even be harmful
2. Nature has evolved an array of Enzyme-catalyzed processes to rid our bodies of these
invading substances.
a. Substances that are foreign to the body are called xenobiotics
b. This study of the biological fate of xenobiotics is what we refer to as Drug Metabolism
3. Basics of drug metabolism
a. Polar substances can be excreted via the kidneys into the urine
b. Most Medicine
Very lipid-soluble
Reabsorbed from kidney tubule back into the blood stream
The whole point of drug metabolism is to have the compounds (medicine)
undergo metabolism, generating polar species which can avoid being
reabsorbed via the renal system and can be excreted via urine
c. Common but misleading to think drug metabolism is just a detoxifying or deactivating
process
Metabolites may actually be similar in pharmacological activity to the parent
1. Nortriptyline, the N-dimethylated metabolite of the antidepressant
amitriptyline
Metabolites may have a life-threatening toxicity
1. Painkiller paracetamol, gets metabolized to a highly reactive species
which damages the liver in overdose
4. The Chemistry of Drug Metabolism
a. The chemical pathways by which drugs are metabolized are extremely varied.
b. Divided into phase 1 and phase 2 reactions
Phase 1 Metabolism
1. Functionalization occurs where a polar grouping is added to or exposed
on the molecule
2. MOST IMPORTANT phase 1 pathway is Oxidation, although other
reactions notably reduction and hydrolysis do occur
3. Cytochrome P450 monooxygenases (CYPs) are the enzymes largly
responsible for drug oxidation
a. Initial reaction is mainly the insertion of a high-energy oxygen
atom into a single C-H or multiple C-C bond, is the same for all
substrates, the end result may be quite different
Phase 2 metabolism
1. These reactions are ones of conjugation in which a polar group possibly
formed during a phase 1 reaction, reacts with an endogenous molecule
(substance that originates from within an organism, tissue, or cell.) such
as glucuronic acid to form a water-soluble product suitable for excretion
2. In some cases, a phase 2 metabolite can be more pharmacologically
active than the parent drug
5. The biochemistry of drug metabolism
a. Sites of metabolism
Enzymes that metabolize drugs are present mainly in the liver although
significant metabolism may take place in the intestines, lungs, or brain as well as
other places.
When a drug is administered orally, the metabolism in the liver may be so
efficient that little or none of the drug enters the systemic blood circulation.
1. Termed the first pass effect
a. Drugs undergoing the first pass metabolism may need to be
administered via a non-oral route.
b. Phase 1 Enzymes
Enzyme Catalyzing phase 1 reactions include
1. CYPs, Flavin monooxygenases, aldehyde oxidases, and epoxide
hydrolases.
2. CYPs (cytochromep450) studied the most
a. Named for ability to absorb light at 450nm in the reduced form
and complexed to carbon monoxide
b. The endogenous (natural) role regulation of steroids,
elcosanoids, and other hormones by oxidative processes
c. Represents a super family of several hundred members
arranged in multigene gene families and subfamilies according
to their amino acid sequence
d. CYPs 1A, 2C, 2D, 2E, and 3A are primarily involved with drug
metabolism in humans
i. A given drug could be a substrate (a molecule upon
which an enzyme acts) for more than one CYP isoform
ii. A single form of CYP may be capable of metabolizing a
range of drugs
1. CYP2D6 metabolizes many widely used drugs
such as antidepressants, antischizophrenic
agents, cardiovascular drugs, pain killers, even
drugs of abuse such as ecstasy.
iii. Various contributions of the CYP isoforms are well
illustrated by Warfarin an anti-blood-coagulant
1. Administered as a racemic mixture (S)-Warfarin
and (R)-Warfarin.
2. (S)-Warfarin is metabolized more quickly via the
major pathway being 7-hydroxylation, CYP2C9
responsible for that.
3. (r)-warfarin is metabolized mainly via 6- and 8-
hydroxylation pathways catalyzed by CYPs 1A1
and 1A2.
iv. Less commonly, CYP and other enzymes act in reductive
roles, substrates include azo and nitro compounds, also
some epoxides
c. Phase 2 Enzymes
Mediated by a diverse group of transferase enzymes (general name for the class
of enzymes that enact the transfer of specific functional groups from one
molecule the donor to another called the acceptor)
1. Include, glucoronosyl transferases, sulfotransferases, and glutathione-S-
transferases
2. There is strong evidence that phase 2 enzymes, notably uridine
diphosphate glucuronosyl transferases (UDPGTs) occur in multiple
forms.
3. UDPGTs require uridine diphosphate glucuronic acid as a cofactor. (Non-
protein chemical compound that is required for the proteins biological
activity. Can be considered helper molecules that assist in biochemical
transformations.)
a. Gets derived enzymatically from glucose and is present / found
everywhere in body tissues
4. Responsible for the conjugation of a range of endogenous molecules
(originate from within an organism, tissue, or cell)
a. Glucuronidation is the most common phase 2 reaction, due to
abundance of UDPGA
i. The addition of glucuronic acid to a substrate (a
molecule upon which an enzyme acts)
ii. Mechanism
1.
This part is confusing what is the relevance? Talk to Dr. Fab tomorrow!
6. Clinical and Industrial Applications
a. Catalytic activities of the drug-metabolizing enzymes, especially CYPs, vary widely
between species and between individuals.
Because of this differing ability to eliminate drugs via metabolism, the
concentration of a drug in the blood and at the tissue where it acts may vary
greatly between individuals given the same dose
Many factors ranging from genetic makeup to lifestyle play a role