Membrane Transport

The Epithelium is the ?

• barrier for absorption

All internal and external body surfaces are lined with ______. Drugs must ______ the epithelium to reach _______ circulation.

epithelium, penetrate, systemic

The epithelium is the __________ barrier for drug absorption in _______ administration.

rate-limiting, non-injection

What is simple squamous epithelium?

• single layer of thin flattened cells

Where is simple squamous found?

• lung’s alveoli

• kidney’s filtration tubule

• somewhat endothelium

What is simple columnar/cuboidal epithelium?

• a single layer of column/cube shaped cells

• ciliated or non-ciliated

Where is simple columnar/cuboidal found?

• stomach

• small intestine

• large intestine

• lung’s bronchioles

• kidney’s distal tubule and collecting duct

What is stratifies squamous epithelium?

• multi-layers of flattened cells with outer cells keratinized or non-keratinized

Where is stratified squamous epithelium?

• oropharynx cavity

• esophagus

• rectum

• vagina

• cornea

• skin

What is pseudostratified columnar epithelium?

• a single layer of columnar cells each which touches the basal lamina directly

• their nucleus location gives the stratified look

Where is pseudostratified coumnar?

• nose

• larynx

• trachea

• urethra

What is transitional epithelium?

• multi-layers of differently-shaped cells that allow stretching

Where is transitional epithelium?

• urothelium of the bladder and ureter

Order the epitheliums in order of cell thickness:

• squamous < columnar/cuboidal

• simple < stratified

What about the epithelial types varies across different body parts?

• cell thickness

• tightness between cell junctions

• functionality of specialized transport

→ influence the kinetics of drug transport at each site

The phospholipid bilayer of the cell membrane is _____ and separates the _____ and ______ cellular aqueous phases.

lipophilic, intra-, extra-

_____ proteins in the lipid bilayer can act as transporters.

integral

Lipophilic molecules are _____ in by the PM, while ______ molecules are repelled.

taken; hydrophilic

What molecules diffuse through a membrane?

• lipophilic molecules

• small, uncharged, polar molecules

What molecules don’t diffuse through a membrane?

• large, uncharged, polar molecules

• ions

What is Fick’s equation adjusted to account for lipophilic molecules?

• D*A*KD*((C1-C2)/h)

Diffusion is faster when?

• D = large (small MW drugs)

• A = large (SI rather than skin)

• KD = large (lipopilic drug)

• C1-C2 = large (high conc/dose)

• h = small (SI rather than skin) -how thick the membrane is

_______ partitioning creates a true conc. gradient for diffusion.

membrane

In membrane partioning what is replaced in Ficks equation?

• C1-c2 is replaced with Cm1-Cm2

• Cm1 = KD*C1

• Cm2 = KD*C2

Inc. KD → inc. _____ as long as drugs are fully _____.

rate of absorption, dissolved

What is the pH-partition hypothesis?

• only unionized, nonpolar drugs can penetrate the cell membrane, ionized species are repelled

• fraction of unionized drugs at the absorption site determines their diffusive permeation across cell membranes

If an acid is in basic conditions it will be?

ionized

*acid

If a base is in acidic conditions it will be?

ionized

*base

If the % of unionized is inc. then the _____ is inc. and the % of _____ is inc.

rate of absorption, absorption

What is paracellular diffusion?

• diffusion pathway made by tight junctions and ECF for hydrophilic or ionized drugs

Hydrophilic and/or ionized drugs diffuse in a _______ or ________ manner without membrane partitioning.

restricted, size-excluded

Transcellular diffusion is for?

• lipophilic unionized small MW drugs

• dependent on D (diffusion coefficient)) and KD (lipophilicity)

Paracellular diffusion is for?

• hydrophilic ionized small MW drugs

• dependent on D (diffusion coefficient)

• restricted based on size of molecule and pathway available

A PK profile of diffusive absorption becomes proportional to what?

• dose

Order of dose routes in terms of diffusion rates (fastest to slowest):

• pulmonary

• nasal

• GI

• rectal

• buccal

• transdermal

The rate of diffusion of drugs through any of the diffusion mechanisms is depended on:

• drug

• membrane

• conc.

Cells must have mechanisms to:

• uptake hydrophilic molecules (carbs, AA, ions)

• remove lipophilic molecules (anti-tumor drug)

Uptake and efflux transporters (also cytosis) make up for the insufficient discrimination of the membrane’s _____ diffusion.

partition-based

What does SLC stand for?

SoLute Carrier

SLC uptake transporter:

• protein-mediated transport of substrate molecules upon binding

• 3 types: uniport, symport, antiport

Uniport - facilitated diffusion:

• passively transported via uniport transporters, following the conc. gradient

• cell E not req.

• significantly greater transport rate than diffusion

• nonlinear and saturable transport rate

• structure-selective and inhibited by chemically similar molecules

In Uniport, the transport rate is Not proportional to conc. because at higher conc. the transporters become _______.

saturated

Symport/Antiport:

• actively transported via proteins against a conc. gradient

• ATP is indirectly used

• nonlinear and saturable transport rate

• structure selective and inhibited by chemically similar molecules

PEP1-mediated GI absorption has inc. absorption when ____ is added, even through it is inc. its ______.

Valine, hydrophilicity

OATP-mediated GI absorption is _______ because of competitive transport inhibition by fruit juices.

reduced

ABC efflux transporters:

• ATP-Binding Cassette protein-mediated efflux transport of substrate molecules upon binding

• actively removed out of cells against conc. gradient

• ATP directly used

• nonlinear and saturable transport rate

• structures selective and inhibited by chemically similar molecules

P-glycoprotien (PgP; MDR1):

• Multi-Drug Resistance efflux proteine expressed in the intestinal epithelium, hepatocytes, renal proximal tubular cells, and brain capillary endothelium

Role PgP plays in intestinal absorption:

• substrate drugs readily enter the cells due to lipophilic nature

• PgP transports the drugs back into the intestinal lumen

• net absorption is reduced, resulting in compromised blood levels

PgP in drug absorption:

• chemically diverse drugs from different classes can act as substrates

• Certain drugs, exipients diets, and supplements can act as PgP inhibitors or inducers

GI absorption of Morphin is a net result of _____ ______ and _____ ___, the latter of which can be inhibited by quinidine.

transcellular absorption, PgP-mediated efflux

Rifampin induces PgP, inc. efflux during _____ and reducing _____ ____.

GI absorption, blood levels.

Small MW drugs are not absorbed by _______/_____.

endocytosis/transcytosis