Absorption

Question 1

What are the three main forms of taking in/absorbing a xenobiotic

Answer 1

Ingestion, Inhalation, and Dermally
(GI tract, Lungs, Skin [intravenously (IV])

Question 2

Lipophilicity

Answer 2

Lipid loving, key feature to allow absorption, allowing to diffuse across cell membrane

Question 3

Hydrophilicity

Answer 3

water loving

Question 4

4 different ways a chemical can cross cell membranes

Answer 4

Passive transport (simple diffusion), Filtration (bulk flow), Facilitated Diffusion, Active transport

Question 5

Passive transport

Answer 5

Chemical follows a concentration gradient across membrane (transcellular diffusion) [MAJORITY]

Question 6

Filtration

Answer 6

passive transport through cell junctions due to pressure gradient (paracellular transport)

Question 7

Facilitated diffusion

Answer 7

Also passive transport following a concentration gradient, BUT requires transporter to assist movement across membrane

Question 8

Active transport

Answer 8

Movement AGAINST concentration gradient, requires ATP

Question 9

What is the most common absorption pathway

Answer 9

Passive transport, xenobiotics simply follow concentration gradients across membrane

Question 10

Organic Lipophilic chemicals,

Answer 10

Diffusion across lipid membrane (transcellular diffusion)

Question 11

How is lipophilicity of chemicals measured

Answer 11

using the octanol: water partition coefficient (Kow) [Kow can be known as “P” as well]

Question 12

High Log Kow value (>4) indicates what?

Answer 12

Significant potential for accumulation and toxicity ie DDT

Question 13

what does POP’s stand for

Answer 13

Persistent organic pollutants
Canadian term, also known as legacy contaminents

Question 14

P = Concentration in organic/concentration in aqueous

Answer 14

take the log of P value to make it an easier number

Question 15

Only what form of the xenobiotic can passively diffuse across cell membranes?

Answer 15

only nonionized forms can

Question 16

which chemicals exist in both ionized and nonionized forms and depends on the pka and ph of the solution?

Answer 16

Weak organic acids and bases

Question 17

what is the henderson-hasselbach equation and what can it be used to determine

Answer 17

log([protonated]/[nonprotonated]) = pka-ph
can be used to determine the ratio of nonionized vs ionized form of the xenobiotic

Question 18

protonated form of an weak acid is what?
protonated form of a weak base is what?

Answer 18

protonated form of acid is NONionized (HA)
protonated form of base is IONized (BH+)

Question 19

what does protonated mean

Answer 19

means it has a proton on it

Question 20

which parts of these equations are ionized and non ionized
HA <-> H+ + A-
B + H+ <-> HB+

Answer 20

HA is nonionized
HB+ is ionized

Question 21

only what form of a drug can readily penetrate cell membranes?

Answer 21

nonionized forms

Question 22

ph 1-6 is…
ph 7 is….
ph8-14 is…

Answer 22

1-6 is acidic
7 is neutral
8-14 is basic

Question 23

ex 2
An antibiotic is a weak base with a pka of 9.5. what are the proportions of the nonionized to ionized forms of the drug in plasma (pH = 7.5) versus breast milk (pH = 6.5)? what is the clinical relevance of this?

Answer 23

log ([protonated]/[unprotonated]) = pka - ph
pka 9.5 - ph 7.5 = 2, log 10- of 2 = 100
pka 9.5 - ph 6.5 = 3, log 10- of 3 = 1000
therefore, the drug is 10x more ionized (protonated) in the more acidic breast milk
the clinical significance is the concept of “ion trapping”. As the nonionized form diffuses into breast milk, the more acidic pH causes more of the drug to be ionized, and thus “trapped”. In this case, treating a mammary gland infection (mastitis) with an antimicrobial drug that is a weak base will result in increased drug concentration at the site of infection and increase efficacy

Question 23

Pka & Ph example question:

What would be more preferentially absorbed from the stomach (pH = 2): a weak acid with pka = 3 or a weak acid with pka = 4?

Answer 23

log ([protonated]/[unprotonated]) = pka - ph
pka 3 - ph 2 = 1, log10- of 1 = 10
pka 4 - ph 2 = 2, log 10- of 2 = 100
therefore, pka 4 is 10x more nonionized at ph2 and thus more preferentially absorbed from the stomach

Question 24

filtration (bulk flow)
how do the xenobiotics move

Answer 24

they move with water through gap junctions between cells due to pressure gradients ie blood pressure
the size of xenobiotic is important
most cells have gaps of 4nm, most blood vessels 2nm, glomerulus 70nm, CNS 0nm, blood brain barrier - tight junction

Question 25

Facilitaed diffusion

Answer 25

important for nutrients and electrolytes; certain xenobiotics can compete for these systems

Question 26

OATs, OCTs

Answer 26

Organic anion transporters
Organic Cation transporters

Question 27

Active transport important for which part of ADME

Answer 27

excretion; brain, liver, kidneys, all have AT systems

Question 28

ABC proteins

Answer 28

ATP-binding cassette - super family

Question 29

Major Familes

Answer 29

MDRs and MRPs
multi-drug resistance proteins
BCRP
Breast cancer resistance proteins

Question 30

lipophilic vacuum cleaners

Answer 30

ABC transporter protein activity - gets sucked back to the outside - never has a chance to pump cells in cause they keep getting sucked back out

Question 31

Where does most absorption occur

Answer 31

GI tract - small intestines due to high surface area

Question 32

Dermal absorption

Answer 32

Skin of mammals is essentially a non-permeable barrier to most chemicals, unless chemical is highly lipophilic or skin is damaged