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X-Phar410 Drug Bio
Drug Biotransformation
| Question | Answer |
|---|---|
| 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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