topic 3 Flashcards
What is biotransformation
term used to describe the process by which the body alters the chemical structure of a chemical foreign to the body.
What are 5 possible consequences of biotransformation?
A biologically active compound converted to an inactive compound (detoxification)
The metabolites become more polar and thus more readily excreted; they become water soluble salts
The metabolites become more biologically active (Metabolic activation). These are “prodrugs” and are more rare.
The metabolites behavior similarly to the parent compound.
The metabolites are more toxic than the parent (acetaminophen, when taken in excess will saturate the glucuronic acid transferase and then the p450 will convert it to a toxic metabolite).
Where does biotransformation occur?
Mainly in the liver, in hepatocytes and mainly in smooth ER, but also some in kidneys, SI, lungs, and nasal epithelium
Generally, what happens in phases 1 and 2
In phase one, oxidation and hydroxylation are what mainly occur, but dealkylation, deamination, and hydrolysis also occur. Overall, a polar metabolite is formed by creating or unmasking a reactive functional group.
In phase 2, that metabolite is conjugated with another, usually by gluconuration, and that usually makes it inactive.
What are microsomes?
They are an artificially generated organelle made after centrifugation consisting largely of SER. It contains P450.
What is P450?
It is a term used to describe a super family of enzymes that catalyze the oxidative metabolism of many endogenous substances and drugs. It is found in all living things.
How are P450 genes classified?
They are listed by CYP, then, There are families (1,2,3, etc.), then subfamilies (A,B,C, etc.) then the genes (1,2,3). So CYP3A4, e.g.
Which P450 families are involved in drug biotransformation and which genes are most important?
Families 1,2, and 3. CYP3A4 does 50% of drugs, CYP2D6 does 25% of drugs, and CYP2C9 and CYP2C19 do 15% of drugs, and CYP1A2 does 5% of drugs.
Why is it important to know about these genes?
CYP2D6 is involved with a lot of antipsychotics, antidepressants, and with codeine. There are also polymorphisms of this gene and others. In some people with a polymorphism, codeine can’t be turned into morphine and thus doesn’t work. It can be very helpful to know the genetic make up of a patient.
What are the steps of the catalytic cycle of oxidation using cytochrome p450?
Drug binds, complex reduced (e- added, fe2+ formed), O2 added, H+ and e- added, H+ added and H2O removed, OH added to drug, drug released.
What oxidations occur independently of cytochrome p450?
Microsomal Flavin-containing MOnooxygenase (FMO),
Alcohol dehydrogenase (ADH)-although it is also metabolized by CYP2E1 though not as much,
xanthine oxidase (amine oxidases and dehydrogenations).
What reductions occur?
Azo reductions (N=N to N+N),
nitro reductions (NO2 to NH2)
carbonyl reductions (C=O to C-OH)
What hydrolysis reactions occurs
esters (COOR to COOH +ROH)
Amides (CONHR to COOH + RNH2)
What types of phase II reactions are there, what is the endogenous reactant, and what is the enzyme?
Glucuronidation (most): UDP Glucoronic Acid, UDP Glucoronyl Transferase
Acetylation: Acetyl CoA, N-Acetyl transferase
Glutathione conjugation: glutathione, GSH-H transferase
Glycine conjugation: glygine, Acyl-Coa Glycine transferase
sulfate conjugation: phosphoadenosyl phosphosulfate, sulfotransferase
Methylation: SAM, Transmethylases
What is induction?
When one drug uses the same CYP enzyme as another, it can induce more enzymes to be made. This can work for pre-treatment too. For example, CYP2E1 can be induced by ethanol, so more CYP2E1 enzymes are formed making ethanol easier to metabolize. We are exposed to various pollutants in air and food that lead to induction of certain CYP enzymes, making the drugs that an individual takes less effective.
Steps of enzyme induction
Increases the rate of hepatic biotransformation of drug
Increases the rate of production of metabolites
Increases hepatic drug clearance
Decreases serum half-life
Decreases serum and total and free drug concentrations
Decreases pharmacological effects if the metabolites are inactive or increases them if metabolizing them activates them.
What is inhibition?
Some drugs will inhibit the function of a P450 enzyme making it not work very well for other drugs that are metabolized by that enzyme which would normally make the other drug more effective b/c it remains in its active form.
What are 3 ways inhibition occurs?
Reversible inhibition: competition of binding
Metabolite intermediate complexion: a metabolite of the drug makes the enzyme inactive.
Autocatalytic inactivation: drug converted to highly reactive radical which inactivates function of enzyme completely.
Drug Drug interactions
Can be very dangerous and are often fatal. At 6 drugs, the drug drug interactions increase logarythmically.
Steps of inhibition of microsomal enzymes
Decreases the rate of hepatic biotransformation
of drug
Decreases the rate of production of metabolites
Decreases total clearance
Increases serum half-life
Increases serum and total free drug
concentrations
Increases pharmacological effects if the
metabolites are inactive
What is first pass metabolism?
Drugs taken orally first go into portal vein system and thus into the liver. Some drugs are greatly metabolized in the liver to the extent that they can’t be taken orally (Nitroglycerin, morphine). Others are greatly metabolized, but the metabolite is active.
Comparison of synth and non synth drug biotransformation for phase 2
see table 17, don’t memorize, just study
Factors influencing biotransformation
see table 18, study, don’t memorize.
what is presystemic biotransformation
metabolism of drugs in GI Tract
What are the 3 steps of renal excretion and what happens in each
glomerular filtration-20% of drug enters the tubule with water (unless it is bound to albumin).
Tubular secretion-There are 2 carrier proteins that are very effective at transferring drug from blood to proximal tubule. one is for acidic compounds, one for basic. They get about 99% of the drug out of circulation.
Reabsorption-In distal tubule, the unionized drug will diffuse back into circulation from tubule.
What is enterohepatic recirculation?
Liver releases conjugated drug into bile duct and then intestine where it is unconjugated and thus reenters circulation to go back to the liver and the cycle continues.
What forms of excretion are there?
Kidney, the liver (similar process to kidney–>feces), lung (breathalizer), milk, sweat.
