Metabolism integral part of pharmacokinetics.

It is important because
pharmacokinetics determines what is happening to the drug. The frequency in
taking drugs and how much drug is given. It helps us to predict what is going to
happen to the drug. Factors such as smoking and genetics affect the
pharmacokinetic and metabolism of the drug.
Pharmacokinetics determine the plasma concentration time curve. Whether the
dose is therapeutic or sub-therapeutic or even toxic.
Metabolism is one of pharmacokinetic processes. Another term is FPE first pass
effect (although there is metabolism which is not part of FPE. FPE = metabolism
occurs mostly in the liver. Anything that is absorbed and drugs happen to be
absorbed if taken orally /or other roots. Before it has a chance to go anywhere or
do anything, has to pass through the liver. Some drugs in the liver, change so
much that do not work)
Metabolism body wastes a lot of energy to change the structures of all
xenobiotics (foreign substances including drugs). The body recognizes the drug
as being foreign and changes it so that it is easier to get rid of it. Eventually the
body gets rid of the drug in the kidneys. For the drug to end up in the kidneys. It
has to be water soluble. Metabolism also called biotransformation, change it
chemically, into a metabolite, changing not breakdown because many
metabolites are much larger than the original drug. To make something water
soluble it has to be able to form hydrogen bonds therefore it has to have
hydroxyl groups (most of the time 70% of metabolism is adding on or freeing OH
groups). [3 examples, do not remember]
Metabolism can occur anywhere in the body. It can occur in the skin. medicines
applied topically can be metabolized on the skin, even in the plasma or lungs
such as when inhaling drugs.
Drugs which are lipophilic tend to be more metabolized than those which are
hydrophilic. A handful of drugs are not metabolized at all and excreted
unchanged. On the other hand sometimes these get complex, such as forming a
lot of metabolites.
DMEs- drug metabolizing enzymes. There are the hepatic microsomal enzymes
found in the liver. Responsible for oxidation and conjugation. Hepatic non
microsomal enzymes (found in liver but not microsomes, acetylation, sulfation,
gsh, alcohol/aldehyde, dehydrogenase, hydrolysis and ox/red), even in the brain
there are extrahepatic microsomal enzymes.
Various families of enzymes [remember few of main examples]. Most
important are the p450. CYP.
CYPs contain various families and subfamilies these cytochromes are based on
heme with a central iron. They absorb uv lights at 450 nm. Mostly found on the
rough endoplasmic reticulum in liver cells. also found in simple invertebrates

organisms even plants. Defend themselves against chemical insults (anything

outside the body). CYP 1,2,3 families [do not know the nomenclature]
Various families can metabolize certain structures. 1 cyp is responsible for
metabolizing aromatic ring etc.
Largest is CYP 3a4-5. Role of CYP enzymes in hepatic drug metabolism. Right
drugs available and normally prescribed. About 33% of all drugs are metabolized
by cyp r4-5. 23% of drugs are metabolized by cyp 2d6 but this accounts for only
2% of liver enzymes (the cyp2d6 in the liver). This leads to saturation,
competition. 2 drugs metabolized by same family of cytochromes.
Examples of drugs metabolized by some CYP [remember just 2-3 the important
ones such as cyp2d6]
Limited amount of CYPs. Metabolism can be divided into 2 processes. Phase 1 is a
simple chemical reaction. Type of oxidation, reduction or hydrolysis to make the
drug more water soluble, to free the OH usually. In phase 2, we have the
conjugation. We conjugate the drug with something found in all cells.
Example aspirin: to make it more water soluble, free the OH. In phase 1
metabolism you have hydrolysis of acetyl link to form OH. You get salicylic acid.
salicylic acid is a drug in its own right, it is still active. [ another example:
Propranolol is a beta blocker used to treat hypertension. The main metabolite as
soon as you take it orally, 70% is converted to 4-OH propranolol which is still
active. A drug is active due to the 3D structure. Lock and key mechanism]
In phase 2 of metabolism the OH on salicyclic acid and one OH from glucose
condense to form 1 large molecule = glucuronide. This is phase 2. Most of the
metabolite in the urine is glucuronide. Testing for drugs in urine you test for
the phase 2 metabolites.
A drug cannot be given orally if you have a high 1st pass effect.
Metabolites can be toxic in the case of paracetamol. Some drugs are pro-drugs.
This means that you give a drug that is not active. It has to be metabolized in
order to be active. Class of drugs used in Crohns disease (autoimmune
condition). Salicyclic acid + sulfasalazine a bond is broken down to release the 2
molecules.
Know which family of cytochromes is going to be metabolized.
Cyp3a4 metabolizes a number of molecules.
CYP2d6- if a patient is taking 2 drugs which are both of them metabolized by CYP
2D6, you would have competition and also CYP2D6 is present in low amounts.
DDI drug-drug interaction (which drug can I not give with what).
Some drugs are CYP450 inhibitors block the action of that enzyme. [plasma
conc time curve graph goes up and down such as for amiodarone. If you give a

cyp inhibitor and you block the action of the enzyme, the parent drug will remain
there longer and it doesnt go down] if you keep giving the enzyme inhibitor you
get accumulation therefore either decrease the dose or change the drug.
Other drugs are not enzyme inhibitors but enzyme inducers. These induce the
metabolism of the drug. In this case the plasma conc time curve goes down
earlier. Barbiturates are inducers used in anesthesia and anti epileptic drugs.
Some drugs are completely enzyme blockers.
[example: diazepam (valium) it is metabolized to (add an OH to form tamazepam
or remove the aliphatic/methyl group from the end forming Ndesmethyldiazepam ). Both of thema re metabolized to form oxazepam.
Temazepam and n-desmethyldiazepam are both drugs in their own right.
Paracetamol has about 12 metabolites. A whole box of panadols can kill you.
Paracetamol: about 60% of it is conjugated straight away with glucose to form
glucuronide. 35% conjugates with sulfate. The other 5% is going to be Nhydroxylated to form N-hydroxy paracetamolw hci is reduced to form another
metabolite. Which either combines with glutathione (4%) forming mercapturic
acid conjugates. The other 1% forms covalently bound paracetamol it is not
aromatic, it is not a benzene ring. The electrons jump all the time to form
something very reactive, free radicals (so reactive that the product covalently
combines with large molecules found in all cells including DNA). These reactions
are happening in the liver. 1% of paracetamol metabolite covalently combine
with DNA, changing structure of DNA therefore mutating the DNA in liver cells.
liver cells stop functioning properly, dysfunction of enzyme systems, impaired
calcium homeostasis and susceptibility of cells to oxidative stress and cell death
occurs. With 2 tablets of paracetamol the body can cope with it. If you take more
(extremely) the pathway becomes saturated and more of this reactive
metabolites form. Paracetamol OD treat it in the first 24 hours with glutathione
so that you shift the reaction back this way, to form more mercapturic acid.
[do not remember all of this]
metabolism depends on function of the liver therefore anything that affects
function of liver, the metabolism is affected. Premature infants cannot all
metabolizing enzymes ready. Gentamicine is an antibiotic remains toxic
therefore do not give to children. It causes ototoxicity -> deafness and problems
with balance. Nicotine is an enzyme inducer. Smoking can induce metabolism of
certain drugs. Even environment can affect it.
Grapefruit juice food-drug interaction because of metabolism. Do not take
medicine with grapefruit juice. It is a cyp 3a4 inhibitor.
St johns wort interacts with drugs, it is an antidepressant.
Isosafrole is a cyp1a1 and cypa1a2 found in natural remedies of HRT.

Interaction of grapefruit juice with felodipine (calcium antagonist used in

cardiovascular problems). [squares are felodipine by itself, the black is with
grapefruit juice. The peak plasma concentration, because you inhibit, the plasma
conc changes form 8 to 50, 5 times as much.
Some people may be fast or slow metabolizers. The amount of enzymes we have
can vary from one patient to another.
2 drugs showing a difference is for ionizaid and hydralyzine. Ionizaid is used in
TB.
Also differences in populations CYP2c19 Africans and Caucasians are poor
metabolizers, in Asians it is about 15%. If you miss certain genes, you can get
toxic effects when taking the drug due to difference in metabolism.
Cyp2d6 you can have up to 1000 times differences (variability) in a population.
Bimodal distribution
Sulaphenazole inhibits tolbutamide metabolism.
Oral Antifungals show alto of drug interaction. Lethal drug-drug interaction was
terfenadin. It was the first long acting non-sedative antihistamine.
Antihistamines used routinely for hay fever. They caused a lot of sedation. The
problem was that in itself it is a pro-drug that is cardiotoxic. To be active it had to
be metabolized through cyp3a4 to form terfenadine carboxylate which is nto
cardiotoxic. After 5 years it was withdrawn from market, they inhibited
metabolism of parent drug and the parent drug remained present in the blood
causing death.