Lecture 4 Flashcards
What are the primary locations of metabolism and elimination?
Hepatobiliary system: liver, gall bladder, bile ducts.
Kidneys
Lungs
Other organs may play a minor role, but the majors are listed above. The liver plays a big role, and the reason is because it is the main site of expression if the phase I drug metabolism enzymes. These have the effect of making the drugs more polar and also in many cases chemically reactive which leads to phase II modifications.
Drug metabolism/ bio transformation
Phase I
Functionalization: making the drug more polar, more chemically reactive. Main classes of receptors: P450 enzymes. Carry out mainly oxidative reactions, as well as hydrolysis and reductive reactions.
Structure of P450
Gets its name from the absorbance at 450 nm when it is bound to
carbon monoxide. Binding of carbon monoxide puts the P450 in its
reduced form. a cytochrome (porferin ring structure) is found at the center of the enzyme. substrate binds adjacent, and in the very center we have an oxygen bound by 4 iron atoms.
Mech and localization of P450
P450 transfers one atom of oxygen, but holds molecular oxygen (2 O atoms). In the cycles of P450 action, it goes through a reduced and oxidized form. The enzyme P450 reductase reduces the oxidized form. P450 is found in the liver, lungs, and kidney, but is more predominantly expressed in the liver. It is a membrane associated protein and is associated with the endoplasmic reticulum. Some say its only associated with the smooth ER, but others argue that it can also associate with the rough ER.
What usually happens before a drug is able to be excreted?
Usually it’s modified chemically in some way and then eliminated.
How can dosing old people lead to altered effects?
When dosing old people, you can see an altered effect because their P450 levels are low. So depending on the modification that would normally take place, the result can either be toxic levels of a drug, or very little drug being metabolized.
General info about P450 mixed function oxidase system
- not well developed until 3-8 weeks after birth.
- 70 genes/ 71 different cytochrome (Cyp) P450 isozymes in humans, 71 different proteins so one is a splice variant.
- many Cyps are inducible.
- Cyp activity decreases with age. Important parameter in drug metabolism.
- Males have higher levels than females (some P459 isozymes are induced by testosterone). Much more significant in rats than in humans.
- each isozyme exhibits significant genetic variation between individuals (genetic polymorphisms).
Genetic polymorphisms in P450 isozymes.
may have different activities based on genetic polymorphisms. there are a wide range of these, so if someone has a genetic modification of one there may be more or less sensitive to the actions of the drug based on the modification thatoccurs and the effect on the drug.
Mono oxygenase reaction
Insertion of one atoms of oxygen into the drug and the other into water.
DH+O2+2e+2H–>DOH+H2O
The P450 cycle
active form of P450 is in its reduced state. Drug binds and susequently oxygen binds. One of the
oxygen atoms gets transfered to the drug and the other remains on the P450. To recycle the P450 there
is a reduction reaction involving the cofactor NADPH and NADPH P450 reductase.
Phase I reactions (in detail)
- aliphatic and aromatic hydroxylation.
- O-Dealkylation
- N-Dealkylation
- S-Demethylation
- Oxidative Deamination
- Sulfoxide Formation
- Desulfuration
- Dehalogenation
Do phase I reactions increase or decrease drug activity?
Depending in the specific reaction taking place, the modification can make the drug more active or less active. This would effect whether you’d want to give the drug at a lower or higher concentration.
How does plasma drug concentration vary as individuals get older?
General trend is towards a longer plasma half-life of a drug in the elderly. So as P450 is decreasing with age, half-life is increasing due to less excretion.
Clinical trials
Phase I: 10 or fewer
Phase II: less than 100
Phase III: more than 100.
Greatest diversity of individuals in phase III.
How does pretreatment with phenobarbital affect the drugs ability to induce sleep?
initial doses prime the body for the challenge dose. So when the drug is properly administered, the
body has a high level of the isozyme that metabolizes it. Sleep time without induction was about twice as
long, higher plasma level in uninduced individuals, and longer half-life as well. This shows that the
action of P450 on this drug is activation. The drugs become more soluble and active, which decreases their
half-life.
The effect of phenobarbital administration on Coumarin-induced inhibition of blood clotting
One issue with induction arrises when more than one drug is being administered at the same
time. In this case a barbituate is given along with an anticoagulant (warfarin: given to patients
at risk for blood clots). Both of these drugs are substrates for the same P450 isozyme, but
the phenobarbital is an inducer of the system (both an inducer and a substrate, whereas
coumarin (warfarin) is just a substrate). Potential for competition. So without any induction
there is competition, but if you start making more of the P450, then that competition should decrease.
So the prothrombin is being modified by the P450 so that it wil lbe secreted from the body more
rapidly. Initially theres a dropdown from jsut giving the drug alone, but you get a greater decrease
if giving it in the presence of phenobarbital, which then starts to reverse because more enzyme becomes
availible which lessens the competition. Eventually the system catches up. Prothrombin time needs to
be maintained in a narrow range, so its dangerous to take both of these at the same time. Need to adjust doses
if they are taken together. Better thing is to switch to different drugs though.
What are some common drug drug interactions resulting from P450 induction?
Inducer: phenobarbitol, rifampicin, griesofulvin, phenytoin, ethanol, carbamazepine.
Drug metabolism enhanced: warfarin, oral contraceptives, corticosteroids.
