Absorption Flashcards
What are the three main forms of taking in/absorbing a xenobiotic
Ingestion, Inhalation, and Dermally
(GI tract, Lungs, Skin [intravenously (IV])
Lipophilicity
Lipid loving, key feature to allow absorption, allowing to diffuse across cell membrane
Hydrophilicity
water loving
4 different ways a chemical can cross cell membranes
Passive transport (simple diffusion), Filtration (bulk flow), Facilitated Diffusion, Active transport
Passive transport
Chemical follows a concentration gradient across membrane (transcellular diffusion) [MAJORITY]
Filtration
passive transport through cell junctions due to pressure gradient (paracellular transport)
Facilitated diffusion
Also passive transport following a concentration gradient, BUT requires transporter to assist movement across membrane
Active transport
Movement AGAINST concentration gradient, requires ATP
What is the most common absorption pathway
Passive transport, xenobiotics simply follow concentration gradients across membrane
Organic Lipophilic chemicals,
Diffusion across lipid membrane (transcellular diffusion)
How is lipophilicity of chemicals measured
using the octanol: water partition coefficient (Kow) [Kow can be known as “P” as well]
High Log Kow value (>4) indicates what?
Significant potential for accumulation and toxicity ie DDT
what does POP’s stand for
Persistent organic pollutants
Canadian term, also known as legacy contaminents
P = Concentration in organic/concentration in aqueous
take the log of P value to make it an easier number
Only what form of the xenobiotic can passively diffuse across cell membranes?
only nonionized forms can
which chemicals exist in both ionized and nonionized forms and depends on the pka and ph of the solution?
Weak organic acids and bases
what is the henderson-hasselbach equation and what can it be used to determine
log([protonated]/[nonprotonated]) = pka-ph
can be used to determine the ratio of nonionized vs ionized form of the xenobiotic
protonated form of an weak acid is what?
protonated form of a weak base is what?
protonated form of acid is NONionized (HA)
protonated form of base is IONized (BH+)
what does protonated mean
means it has a proton on it
which parts of these equations are ionized and non ionized
HA <-> H+ + A-
B + H+ <-> HB+
HA is nonionized
HB+ is ionized
only what form of a drug can readily penetrate cell membranes?
nonionized forms
ph 1-6 is…
ph 7 is….
ph8-14 is…
1-6 is acidic
7 is neutral
8-14 is basic
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?
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
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?
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
filtration (bulk flow)
how do the xenobiotics move
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
Facilitaed diffusion
important for nutrients and electrolytes; certain xenobiotics can compete for these systems
OATs, OCTs
Organic anion transporters
Organic Cation transporters
Active transport important for which part of ADME
excretion; brain, liver, kidneys, all have AT systems
ABC proteins
ATP-binding cassette - super family
Major Familes
MDRs and MRPs
multi-drug resistance proteins
BCRP
Breast cancer resistance proteins
lipophilic vacuum cleaners
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
Where does most absorption occur
GI tract - small intestines due to high surface area
Dermal absorption
Skin of mammals is essentially a non-permeable barrier to most chemicals, unless chemical is highly lipophilic or skin is damaged
