Term
| Carrier-mediated transport using influx transporters and efflux pumps occur across barriers of the body (5) and excretory tissues (2). Name them. |
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Definition
Intestine, Blood brain barrier / capillaries of the brain, ovaries, testis, placenta
Livery, kidney. |
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Term
| Vesicle-mediated transport occurs where and in what form? |
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Definition
Endocytosis - Peyer's patches of small intestine
Potocytosis - caveolae
Exocytosis - clathrin-coated pits |
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Term
| Where does passive transport happen in the body? |
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Definition
| Everywhere. It is ubiquitous. Bilayers are present in each body part. |
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Term
| There is no ____ effect with increasing concentration in passive transport. |
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Definition
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Term
| The rate of passive transport is dependent on the ____ and the ____. |
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Definition
pKa and partition coefficients
Continuous rate changes with structure vs abrupt rate changes in carrier-mediated with a small structure change |
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Term
| Facilitated diffusion proceeds across trans-membrane proteins in both directions and without a direct use of energy. State 2 characteristics of facilitated diffusion. |
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Definition
(1) Along concentration gradient.
(2) Can go against concentration gradient for influx of cations and efflux of anions using inside-negative membrane potential. |
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Term
| Which is usually more selective in active transport, influx or efflux? |
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Definition
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Term
| What is a D-glucose influx carrier? |
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Definition
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Term
| Name a peptide influx carrier. |
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Definition
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Term
| Name a nucleotide influx carrier. |
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Definition
| ENT1, ENT2 (e for equilibrative) |
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Term
| Name an organic cation and an organic anion influx carrier. |
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Definition
Cation - OCTs and OCTNs (N for novel)
Anion - OATs and OATPs (P for peptides)
*notice that all the transporters are almost directly named after what they are delivering. Peptide - pept1, nucleotide - equilibrative nucleotide transporter, oct - organic cation transporter, etc. |
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Term
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Definition
Urate - URAT1 - in active renal secretion
Bile salts - BSEP (export pump) in biliary excretion |
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Term
| Efflux pumps are of the ABC gene family. Influx and efflux carriers are of the SLC gene family. What do these acronyms stand for? |
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Definition
SLC - solute carrier
ABC - ATP binding casette |
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Term
| Describe efflux pumps and name two examples. |
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Definition
THey have low specificity and are involved in the resistance to several anticancer drugs.
(1) P-glycoprotein (P-gp or PGP)
(2) multidrug resistance proteins (MRPs) |
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Term
| What is the lag time in relation to flux? |
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Definition
The time it takes for the drug to effect the patient.
Pause between the start of transport and the appearance of the drug on the other side of the membrane. |
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Term
| What is Fick's First Law fo Diffusion? |
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Definition
| Approximate description for sink conditions (the concentration in the acceptor compartment is zero). |
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Term
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Definition
| The drug amount passing through the unit of area in the unit of time. Measure in mass/(areaxtime) |
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Term
| State the equation for flux and define the variables. |
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Definition
J = Dm x Pm x Cd / h
J = flux
Dm = diffusion coefficient of the compound in the lipid
h = thickness of mebrane
Cd = concentration in the donor compartment (vehicle)
Pm = the partition coefficient in the system membrane lipids/water |
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Term
| Flux is also J = PC x Cd. What is PC (mathematically and define)? |
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Definition
| PC stands for permeability coefficient. it is mathematically equal to Dm x Pm / h. It does not account for drug accumulation. |
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Term
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Definition
PC is suitable only for drugs that do not interact with the bilayer.
PC can be used to characterize the initial rate of transport but not to describe the total time course of drug concentrations.
PC is a robust parameter, used also to characterize the drug transport through biological films (intestine, bladder, skin). |
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Term
| The bilayer can be asymmtric due to what 2 variables? |
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Definition
| Different fatty acid chains and different phospholipids (headgroups). |
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Term
| From the viewpoint of the drug transport, the bilayer is ____. |
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Definition
Symmetrical.
Even if, in actuality, it is asymmetrical. The physical properties of 2 monolayers are similar even if they have different composition. |
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Term
| Accumulation of drugs in the bilayer region is characterized by what 3 drug properties? |
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Definition
| Lipophilicity, amphiphilicity, and cephalophilicity. |
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Term
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Definition
| It is the tendency to accumulate in the hydrophobic core of the bilayer. It is expressed as the 1-octanol/water partition coefficient (P). |
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Term
| What is the amphiphilicity? |
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Definition
| It is the tendency to adsorb to the headgroup/core interface. |
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Term
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Definition
| It is the tendency to interact with the headgroups. |
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Term
| What is Ii and what is Io? |
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Definition
Ii is the rate parameter from water --> membrane.
Io is the rate parameter from membrane --> water. |
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Term
| In 1978, Kubinyi stated that trans-bilayer transport rates of non-amphiphilic compounds depends only on ____. |
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Definition
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Term
| Describe the properties of Ii and Io. |
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Definition
| Ii (the rate from water > membrane) increases as the partition coefficeint increases (larger hydrophobic). Io (the rate from membrane to water) decreases as P increases. |
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Term
| The dependencies log c vs. log P for individual times are intiailly ____ with slopes _____ and ____. |
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Definition
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Term
| For equilibrium, the slopes are _____ and ____. |
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Definition
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Term
For log c vs. log P graphs, the peak becomes __a_ after each addition of the bilayer. THe series of bilayers exhibits the _b____. The drugs with __c__ diffuse at the fastest speed.
The slopes of the bilinear portions are equal to __d___. In other words the absolute value of the slope is equal to __e___. |
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Definition
(a) narrower
(b) sieving effect
(c) Po
(d) n-1/2) and (1-n/2). n = compartment #
(e) the number of crosses bilayers |
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Term
| Since the axes of logc and logP are logarithmic, each added bilayer (2 layers) causes a ________ in selectivity. |
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Definition
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Term
| A good estimate of the number of membranes the drug molecules need to cross is __a___. |
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Definition
| A) The number of cell layers x 10. |
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Term
| Name the number of cell layers for the lungs, kidneys, intestines/liver/heart/brain/spleen, and skin/mucsles/fat/bones. |
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Definition
lungs = 1
kidneys = 2
Intestines, liver, heart, brain, spleen = 5
Bones, fat, skin, muscles = 15 |
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Term
| Transport competes with _____. |
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Definition
| Metabolism. The drug can be metabolized in every compartment it passes through. Transport diminishes the concentrations available for metabolism, and vice versa. |
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Term
For lipophilicity, a large throughput was acheived using a surrogate phase (1-octanol or n-hexadecane[C16]) imitating the solvation properties of the core. __a__ represents more than 50% of mammalian phospholipids.
Therefore, the ideal surrogate phase for the headgroups is __b__. |
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Definition
(a) phosphatidylcholine
(b) phosphatidylcholine with the fatty acid chains shortened to acetyls (DiAcetyl PhosphatidylCholine - DAcPC) |
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Term
| So, if C16/water is used for lipophilicity, and DAcPC/water is used for cephalophilicty, then _____ is used for amphilicity. |
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Definition
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Term
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Definition
| A white powder with good solubility in water. |
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Term
| DAcPC forms __a__ liquid after adding __b__ molecules of water per headgroup to achieve __c__. |
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Definition
(a) clear, slightly viscous
(b) 8-16
(c) hydration similar to that of the fluid bilayer. |
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Term
| Hydrated DAcPC is ____ with n-hexdecane / C16. |
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Definition
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Term
| Since DAcPC and water are miscible, we must use the ratio of the two partition coefficient __a__ over __b__ |
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Definition
| (a) C16/water over (b) C16/DAcPC |
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Term
| The drugs that are supposed to have oral bioavailabilty and fast general distribution in the body should have __. |
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Definition
| inermediate lipo, amphi, and cephalo. |
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Term
| The drugs designed for limited distribution close to the site of administration or release from a dosage form should have ____. |
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Definition
| low or high lipo, amphi, and cephalo |
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