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X-Phar410 Drug Bio

Drug Biotransformation

two primary ways in which drugs are eliminated from the body excreted unchanged in the urine or feces; or metabolized or biotransformed and then excreted
second source of metabolism; second to liver intestine
once in bloodstream, drugs are transported directly to liver; first pass metabolism
Biotransformation metabolism
drugs that are "foreign to body" xenobiotics
metabolite derivative of drug structure; usually inactive or less active
biotransformation result in a metabolite that is no longer able to produce a therapeutic response also makes the drug more soluble for excretion
In some cases, the drug is inactive and the biotransformation results in an active compound
want to make the xenobiotics more polar to excrete excreted in urine or feces OR metabolized or biotransformed and then excreted; may also be eliminated through sweat or respiration
most drugs are biotransformed prior to excretion because they are not polar enough to be excreted (not water soluble enough)
most often the product of biotransformation of body enzymes is less active or inactive as compared to parent drug; metabolite can no longer produce therapeutic response
in some cases biotransformation results in an active form of the initially inactive parent drug
inactive parent drug prodrug; must be biotransformed to have therapeutic response
the liver can make more polar in order to excrete but it cannot cant actually make more or less active
biotransformation occurs mainly in the liver; sometimes in kidneys GI tract, skin or lungs
drugs that are ingested orally must first be absorbed in the GI tract to enter bloodstream; once in bloodstream drugs are transported directly to liver via hepatic poral vein then to circulation
a considerable percentage of of an orally ingested dose is often metabolized prior to reaching systemic circulation
the loss of drug due to GI tract biotransformation "first pass"- through liver
an active drug can go two routes directly to excretion or can be biotransformed to an inactive metabolite then excreted
at site of action the chemical structure is not active prodrug; when metabolized it then becomes active
if something is in the small intestine it is technically not "in the body"
orally ingested drugs go to --> intestine --> portal vein --> liver --> circulation via hepatic vein
first pass may or may not happen no way to tell; can be a barrier to get drug into bloodstream
enzymes found in high concentration in liver (lower concentrations in brain, kidneys, intestines, and lungs) CYP450's; superfamily thats responsible for majority of all drug biotransformations
cytochrome P450's are heme containing proteins that are capable of the following rxn's hydroxylations; N, O, and S dealkylations; N-oxidations Sulfoxidation; N- hydroxylation, and deamination(removal of amine)
enzyme involved in drug-drug interactions CYP 450 (1-3)
a substance (drug) that stimulates synthesis of an enzyme; increases metabolic capacity for that isozyme is known as Inducer; induction
competitive binding at an enzymes binding site inhibition
a drug with a high affinity for an enzyme will slow the metabolism of any lower affinity drug at that enzyme basically the high affinity drug will hog the active sites and the low affinity drugs wont be metabolized
when less enzymes are available what happens to drug concentration in bloodstream? It increases because not enough enzymes to metabolize them
affected drugs drugs that are affected by the actions of inhibitors and inducers
block enzymes; prevents other drugs from binding inhibitors; less enzymes= less metabolism
increases amount of enzymes inducers; leads to lower concentrations of the drug in the bloodstream
must abundant subfamily of human cytochrome enzymes CYP3A
administered as inactive drugs prodrugs; it is then transformed into an active substance either by chemical or metabolic means
designed to take advantage of absorption or metabolic properties to provide optimal drug therapy Prodrugs; can be activated in various places (stomach, intestine, liver, inside cell) and in various ways (cleavage of groups, biotransformations, addition of phosphates)
esters in blood can activate prodrugs true; ex:chloramphenicol succinate is chemically inactive until release into bloodstream (IV)
some inactive drugs that cause stomach upset can be matched up with enzymes in the liver that activate them this helps keep the inactive form from stomach upset; it becomes active in the liver
EX: an increase in the plasma concentration of a drug occurs because of inhibition; too many drugs and not enough enzymes
EX: a decrease in the active form of a drug occurs when there is an inducer; more enzymes, more metabolism
EX: Increase in plasma concentration of the ACTIVE form of a PROdrug Inducer; lots of enzymes to activate the prodrug
EX: a decrease in the plasma concentration of the active form of PROdrug inhibitor; not enough enzymes to activate the inactive prodrug
If a genetic defect in a CYP3A4 that made it inactive would result in? No metabolism because enzyme doesnt work
2 types of biotransformations Phase I and Phase II
Functional Phase Phase I; introduce or expose a functional group on a compound to make more polar (hydrophilic)
Phase that generally results in loss of activity Phase I; in some cases the reaction enhances activity of parent compound
BioSYNTHETIC reactions that result in covalent linkage; something is ADDED (conjugated) Phase II; covalent linkage between functional group ON the parent drug and a highly polar conjugate; to make more hydrophilic
Phase I doesnt always happen, neither does Phase II Not always in order of I then II
entero intestine
Microflora in intestines can cleave the covalent bond made during Phase II biotransformations which does what? the parent compound is cleaved and released/ reabsorbed in systemic circulation; enterohepatic recirculation
Reversal of Phase II rxn enterohepatic recirculation; occurs with Glucuronides of drug taht are formed in the liver; excreted in intestine via bile
Phase I reactions (dealkylation)KNOW* N and O- dealkylation (removal of alkyl attached to N or O)
Phase I reactions (hydroxylation) Aliphatic and aromatic hydroxylation- addition of OH group; can also result in a doubly bonded O
Phase I reactions (oxidation) N and S; addition of O to N or S
Phase I reaction (deamination) remove amine; done via oxygen
Phase I reaction (hydrolysis) breaking of a bond with addition of H2O
Phase II reactions Glucuronidation O-UDP + ROH --> RO ; UDP is a transfer agent
Phase II- sulfation add a sulfate (SO3--)
Phase II- Acetylation SCoA + RNH2 --> NHR plus CoASH
Phase II Glutathione conjugation a tripeptide of glutamate, cysteine, and glycine that picks things up to help them be excreted
Glutathione (GSH) is found where? Primarily kidneys and liver in high concentrations; detoxification of xwnobiotics via Phase II conjugation
GSH is metabolized to what in order to be excreted? Mercapturic acids
CSH conjugation is catalyzed by glutathione S- transferases
Electrophilic substrate that wants electrons "E", can be dangerous; we want to bind it to Glutathione and get rid of it
Glutathione Adduct or Conjugate is what The "E" bound to the "S" of the Glutathione; rxn kicks off glutamyl AA and then Glycine AA to leave Cysteine with the E
Mercapturic Acid urinary excretion product; cysteine with the "E" and C=O- CH3
metabolism of acetaminophen 60% Glucuronide, 30% Sulfate -->both go toward renal excretion
Oxidized Acetaminophen becomes NAPQI; "E", can kill hepatic cells if not conjugated with Glutathione
Created by: angieryx



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