ADME 3 - Tavalin Flashcards
What is biotransformation?
chemical modification of xenobiotics by endogenous enzymes
What is the michaelis-menton equation?
V = vmax * [S]/(km+[S])
What is a Phase I reaction?
functionalization reactions. Usually converts the parent drug to an inactive metabolite by introducing or unmasking a functional group. In some cases activity is only modified or even increased (prodrugs). Often times the resulting products are highly reactive and potentially toxic.
What is a Phase II reaction?
leads to covalent addition of a functional group onto the parent comound or the reactive product of a phase I reaction. They are usually inactive and readily excreted.
Where is the main site of biotransformation?
Liver. Can occur in virtually every tissue to some extent though.
Where does subcellular metabolism occur?
Most occurs in the ER and cytosol. Some can happen in the mitochondria, nuclear envelope and plasma membrane.
What is a microsome?
fragment of the ER that contains enzymes and drugs.
Where do most phase I reactions take place?
In the ER
Where do the enzymes responsible for phase II reactions generally exist?
in the cytosol
What is an oxidation reaction? Where does it occur? Is it phase I or II?
Oxidation is a phase I reaction that primarily occurs in the ER. It involved the addition of an oxygen or the removal of hydrogen.
examples: alkyl group to alcohol, aromatic ring to phenol, S or N to sulfoxide or nitroxides
What is a reduction reaction? Is it Phase I or Phase II?
Reduction is a phase I reaction that involves addition of hydrogen or removal of oxygen.
Ex: azo or nitro gourps to amines
What is a hydrolysis reaction? Where does it occur? Is it Phase I or Phase II? What enzymes catalyze it?
Addition of water with breakdown of molecule. Performed in blood plasma and liver by esterases.
Phase I
Ex: Esters -> alcohol and acid
What is glucuronidation? Where does it occur? Phase I or Phase II? What enzymes catalyze it?
the main conjugation reaction in the body. occurs in the liver.
Phase II
catalyzed by UPD-Glucoronsyl transferases (UGTs)
Aliphatic alcohols and phenols are commonly conjugated with glucuronide.
What type of reaction is acylation: I or II? Are its products typically more or less water soluble?
Phase II. Typically less water soluble.
What type of reaction is Glycine addition?
Phase II
What is glutathione (GSH) reaction? Phase I or II. Are its products more water or lipid soluble.
conjugation of tripeptide of glu-cys-gly that leads to a mercapturic acid metabolite that is more water soluble, and less lipid soluble.
What does the CYP3A subfamily do?
metabolizes many drugs during absorption form the GI tract, where it decreases the bioavailability.
Describe the cytochrome-P450 enzyme complex.
Consists of a CYP450 enzyme and reductase.
1 oxygen is added to the drug and 1 atom of oxygen is reduced from H20.
NADPH is the only energy source, no ATP
What is induction?
When drugs promote their own metabolism or the metabolism of other drugs.
Ex: Phenobarbital induces metabolisim of itself and other drugs, requiring huge doses for chronic treatment.
What is inhibition?
When drugs inhibit metabolism of themselves or other drugs.
Ex: warfarin eliminates tolbutamide which can lead to accumulation of drug and requires downward adjustmen.
What are the mechanisms of inhibition?
competition among substrates
Inactivation by formation of a tight complex with heme
depletion of cofactors (more common with Phase II)
enzyme inhibitors
increased degradation.
What enzyme family does grapefruit juice inhibit?
CYP3A family
Concerning polymorphisms, how many different response populations will a monogenic trait (one which has only one changed segment) produce?
A monogenic trait generally produces two response curves: one with the change and one without.
How many response populations would a polygenic trait produce?
a polygenic trait would produce a massive bell curve response due to the multiple combinations of response frequencies.
