lecture 1b: absorption, distribution, metabolism, and excretion (ADME)

what are the important criteria of toxicity? specific toxic effects, __________ to the target (eg receptor binding, targeting particular mechanism), _______ of exposure (oral), distribution to the body/organ, detoxification, easiness to be _________ from the body

selectivity, route, excreted

what is the acronym ADME?

Absorption, Distribution, Metabolism, Excretion

what is Absorption? it is the ______ of exposure so like the form. this could be:

• skin (dermal), GL tract (oral), respiratory tract (inhalation), injection (blood), wound (blood), placenta (fetus, during pregnacy), mucus

all to the __________

route, blood

what is the rate of absorption? how quickly a toxicant reaches the __________. this can depend on the route of exposure:

intravenous (i.v.) > ________ > oral > ___________

blood, inhalation, dermal

the rate of absorption is very critical! absorption depends on the _______ of administration. how _________ a toxic agent reaches the _______ circulation

route, quickly, blood

what is distribution? once the toxicant enters the blood circulation, it will be distributed throughout the body. ______ will it be distributed from the blood circulation? what are the __________? what determines its distribution to the _______ organs? distribution of toxicants is ___________

how, limitations, target, reversible

what are some factors that affect the distribution? ________-limited tissue distribution and tissue _________

perfusion, affinity

what is perfusion-limited tissue distribution? the _______ of blood flow to _________ determines distribution. highly perfused tissues are more _________ (liver, kidney, lung, brain) while poorly perfused tissues are ________ vulnerable (skin, fat, bone)

rate, organs, vulnerable, less

what is tissue affinity? this is ___________, fat tissues (lipophilic toxicants), bones (Pb), and liver (aflatoxin)

transport

describe normal blood capillaries (fenestrated). small _______ in capillary wall, allows penetration of small ________ molecules in blood (100A or smaller), lipophilic molecules _______ permeate capillary wall

gaps, hydrophilic, can

describe brain capillaries (unfenestrated). sealed by _______ junction = BBB or blood-brain ________. hydrophilic molcules ______ permeable, lipophilic molcules can permeate through BBB by ________ (passive transport). efflux transporters are located on the blood side to move xenobiotics back to the blood

tight, barrier, not, transcytosis

distribution also involves the crossing of the plasma _________ of target cells. key properties of the toxicant are hydrophilic vs. hydrophobic aka ___________

membrane, lipophilic

what is a covalent bond (molecular bond)? chemical bonding btw ________ atoms by sharing 2 ________

two, electrons

atoms forming covalent bonds are generally __________ on their own because their _______ ring of electrons are not ________

unstable, outer, filled

water is not a _______ molecule but it is a ________ molecule

charged, polar

charged molecules aka _______ and ______ molecules like sugar are water soluble/hydrophilic because water molecules can surround and segregate them from each ________

ions, polar, other

__________ molecules aka _________ bonding are not water soluble/hydrophobic or lipophilic

non-polar, covalent

key rule for distrbution: if the substrate is __________, then it readily crosses the plasma membrane and enters the cell: the final ____________

lipophilic, destination

if a toxicant is lipophilic, it can easily cross the membrane through simple _________

diffusion

if simply diffusion does not work, toxicants could enter the cell through other ways but could be limited entry:

1. simple diffusion

2. passive _________ (facilitated diffusion)

3. active transport

4. endocytosis (pinocytosis, phagocytosis)

transport

toxicant with _________ chemical structures and/or physical property with the ligand = may be able to use exisitng ________ and _________

similar, channels, transporters

what determines distribution?

cells are all protected by plasma membranes and membrane expresses various channels and transporters to transport molecules across the membrane. some organs have extra _________ to limit the movement of substrates (BBB)

with toxicants, __________ molecules are more readily distributed throughout the body than hydrophilic molecules, possessing a huge advantage

protections, lipophilic

describe metabolism. it is the way of _________. the ________ is the primary organ to metabolize toxicants. phase I and II metabolism, changes chemical ___________ from ________ soluble to more ________ soluble

detoxification, liver, structure, lipid, water

what are inorganic compounds? chemical substances ___________ carbon-hydrogen bonds (_____)

lacking, C-H

what are organic compounds? chemical substances with _______-__________ bonds

carbon, hydrogen

toxic substances are generally ________ chemicals, making them readily _________ from the GI tract, lung, skin, and other routes and ________ throughout the body (entering the cell)

lipophilic, absorbed, distributed

the body has to convert toxic substances to more water-soluble __________ chemicals, so that they are readily _________ from the body via urine or bile

hydrophilic, removed

there are 2 steps of metabolism, phase I and phase ____ and this is _________

II, irreversible

what occurs in phase I metabolism? adding _______ _________ groups such as -OH, -SH, -NH2

small, polar

what occurs in phase II metabolism? adding a ________ polar or ________ molecule to substantially ___________ water-solubility of the metabolites. transferases are responsible for this reaction (conjugation reaction)

large, charged, increase

describe phase I metabolism: ___________. adding _______ molecule and __________ the ________ bond of the substrate

hydrolysis, water, breaking, covalent

describe phase I metabolism: dehydrogenation. this is when the end product becomes more water _________

soluble

what is phase I metabolism by cytochrome P-450 (CYP)? the target carbon (C) and add _________ group (-OH). the target carbon-carbon double bond (C=C) and add ________ (O) atom which is the epoxide formation. we then replace ________ (S) with oxygen atom (O)

hydroxyl, oxygen, sulfur

what is dehalogenation by CYP? it is removing __________ atom(s) like F, CI, Br, I. this is important because the presence of halogens may significantly _________ chemical ___________ (hard to be broken down) in the environment and in the body. but this is an extremely ________ process

halogen, increase, stability, slow

in phase I metabolism, why is it important to add these small polar groups? because electron rich atoms with paired electron(s) are looking for atoms with _______ in electron density while ________ with deficit in electron density are looking for _______-rich atoms. this means that they are __________

deficit, carbon, electron, reactive

phase I metabolism adds _____ ______ groups (-OH, -SH, epoxide, etc) to the _________ to make it a little more water-_________ and more _________ for phase II metabolism

small, polar, substrate, soluble, reactive

what is phase II metabolism? it consists of __________ reactions. this is adding a _______ polar molecule or a charged molecule to the substrate to make it very ____________. enzymes responsible for phase II metabolism are __________

conjugation, large, hydrophilic, transferases

examples of phase II metabolism are _____________ by UDP-glucuronosyltransferases, __________ by sulfotransferases, and ___________ (GSH) conjugation by glutathione transferases

glucuronidation, sulfonation, glutathione

describe excretion. all mechanisms of __________ of toxicants from the body. by _________, lung, ______ tract, and others (sweat, tears) excretion through milk is a risk of __________ exposure of toxicants

elimination, kidney, GI, secondary

Clearance (CL) is defined by: CL (total) = CL (GI tract) + CL (________) + CL (other)

kidney

describe urinary excretion. glomerular filtration and tubular excretion by __________ diffusion and _________ tubular secretion. __________ toxicants are re-________ back to the __________ efficiently. ________, water ________ toxicants are excreted with urine (AVG. pH6-6.5). _________ bases are easily excreted with urine

passive, active, lipophilic, absorbed, blood, polar, soluble, weak

describe fecal excretion. this is with non-_______ ingested toxicants. biliary excretion is absorbed toxicant being transported from the blood to ___________, where it is metabolized by phase I and phase II reactions, and excreted into the bile duct

absorbed, hepatocytes