Drug Biotransformation
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| 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
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| second source of metabolism; second to liver | intestine
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| once in bloodstream, drugs are transported directly to | liver; first pass metabolism
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| Biotransformation | metabolism
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| drugs that are "foreign to body" | xenobiotics
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| metabolite | derivative of drug structure; usually inactive or less active
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| biotransformation result in a metabolite that is no longer able to produce a therapeutic response | also makes the drug more soluble for excretion
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| In some cases, the drug is inactive and the biotransformation results in | an active compound
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| 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
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| most drugs are biotransformed prior to excretion because they are not | polar enough to be excreted (not water soluble enough)
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| 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
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| in some cases biotransformation results in | an active form of the initially inactive parent drug
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| inactive parent drug | prodrug; must be biotransformed to have therapeutic response
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| the liver can make more polar in order to excrete but it cannot | cant actually make more or less active
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| biotransformation occurs mainly in the | liver; sometimes in kidneys GI tract, skin or lungs
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| 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
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| a considerable percentage of of an orally ingested dose is often metabolized | prior to reaching systemic circulation
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| the loss of drug due to GI tract biotransformation | "first pass"- through liver
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| an active drug can go two routes | directly to excretion or can be biotransformed to an inactive metabolite then excreted
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| at site of action the chemical structure is not active | prodrug; when metabolized it then becomes active
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| if something is in the small intestine it is technically | not "in the body"
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| orally ingested drugs go to --> | intestine --> portal vein --> liver --> circulation via hepatic vein
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| first pass may or may not happen | no way to tell; can be a barrier to get drug into bloodstream
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| 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
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| 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)
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| enzyme involved in drug-drug interactions | CYP 450 (1-3)
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| a substance (drug) that stimulates synthesis of an enzyme; increases metabolic capacity for that isozyme is known as | Inducer; induction
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| competitive binding at an enzymes binding site | inhibition
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| 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
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| when less enzymes are available what happens to drug concentration in bloodstream? | It increases because not enough enzymes to metabolize them
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| affected drugs | drugs that are affected by the actions of inhibitors and inducers
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| block enzymes; prevents other drugs from binding | inhibitors; less enzymes= less metabolism
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| increases amount of enzymes | inducers; leads to lower concentrations of the drug in the bloodstream
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| must abundant subfamily of human cytochrome enzymes | CYP3A
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| administered as inactive drugs | prodrugs; it is then transformed into an active substance either by chemical or metabolic means
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| 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)
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| esters in blood can activate prodrugs | true; ex:chloramphenicol succinate is chemically inactive until release into bloodstream (IV)
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| 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
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| EX: an increase in the plasma concentration of a drug occurs because of | inhibition; too many drugs and not enough enzymes
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| EX: a decrease in the active form of a drug occurs | when there is an inducer; more enzymes, more metabolism
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| EX: Increase in plasma concentration of the ACTIVE form of a PROdrug | Inducer; lots of enzymes to activate the prodrug
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| EX: a decrease in the plasma concentration of the active form of PROdrug | inhibitor; not enough enzymes to activate the inactive prodrug
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| If a genetic defect in a CYP3A4 that made it inactive would result in? | No metabolism because enzyme doesnt work
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| 2 types of biotransformations | Phase I and Phase II
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| Functional Phase | Phase I; introduce or expose a functional group on a compound to make more polar (hydrophilic)
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| Phase that generally results in loss of activity | Phase I; in some cases the reaction enhances activity of parent compound
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| 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
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| Phase I doesnt always happen, neither does Phase II | Not always in order of I then II
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| entero | intestine
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| 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
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| Reversal of Phase II rxn | enterohepatic recirculation; occurs with Glucuronides of drug taht are formed in the liver; excreted in intestine via bile
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| Phase I reactions (dealkylation)KNOW* | N and O- dealkylation (removal of alkyl attached to N or O)
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| Phase I reactions (hydroxylation) | Aliphatic and aromatic hydroxylation- addition of OH group; can also result in a doubly bonded O
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| Phase I reactions (oxidation) | N and S; addition of O to N or S
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| Phase I reaction (deamination) | remove amine; done via oxygen
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| Phase I reaction (hydrolysis) | breaking of a bond with addition of H2O
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| Phase II reactions Glucuronidation | O-UDP + ROH --> RO ; UDP is a transfer agent
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| Phase II- sulfation | add a sulfate (SO3--)
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| Phase II- Acetylation | SCoA + RNH2 --> NHR plus CoASH
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| Phase II Glutathione conjugation | a tripeptide of glutamate, cysteine, and glycine that picks things up to help them be excreted
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| Glutathione (GSH) is found where? | Primarily kidneys and liver in high concentrations; detoxification of xwnobiotics via Phase II conjugation
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| GSH is metabolized to what in order to be excreted? | Mercapturic acids
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| CSH conjugation is catalyzed by | glutathione S- transferases
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| Electrophilic substrate that wants electrons | "E", can be dangerous; we want to bind it to Glutathione and get rid of it
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| 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
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| Mercapturic Acid | urinary excretion product; cysteine with the "E" and C=O- CH3
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| metabolism of acetaminophen | 60% Glucuronide, 30% Sulfate -->both go toward renal excretion
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| Oxidized Acetaminophen becomes | NAPQI; "E", can kill hepatic cells if not conjugated with Glutathione
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