1 absorption

Question 1

what is toxicokinetics?

Answer 1

-toxicokinetics: determination of the time course of disposition (ADME) of xenobiotics in the body (WHAT THE BODY DOES TO THE XENOBIOTIC)
-determines the concentration of xenobiotic at its site(s) of action, and thus is linked to the intensity of biological effect

Question 2

what is the schematic diagram of ADME?

Answer 2

Question 3

what is the more detailed diagram of ADME?

Answer 3

Question 4

what are animal cell membranes?

Answer 4

phospholipid bilayers

Question 5

is lipophilicity important?

Answer 5

-the lipophilicity (lipid solubility) of a xenobiotic is the most important factor allowing it to diffuse across cell membranes (molecular size is also important)

Question 6

what are the ways in which chemicals cross cell membranes?

Answer 6

-passive transport (simple diffusion) (most important)
-filtration (bulk flow)
-facilitated diffusion
-active transport

Question 7

what is passive transport?

Answer 7

-chemical follows a concentration gradient across cell membrane
-termed transcellular diffusion
-most common absorption pathway for all xenobiotics

Question 8

what is filtration (bulk flow)?

Answer 8

-passive transport through cell junction dues to pressure gradient
-termed paracellular transport

Question 9

what is facilitated diffusion?

Answer 9

-also passive transport following a concentration gradient, but requires transporter to assist movement across membrane

Question 10

what is active transport?

Answer 10

-movement against concentration gradient
-requires ATP

Question 11

what is simple diffusion of organic lipophilic chemicals?

Answer 11

diffusion across lipid membrane (transcellular diffusion)
-lipophilicity of chemicals is measured using the octanol: water partition coefficient (KOW)
-high log Kow value (>4) indicates significant potential for accumulation and toxicity (extremely lipophilic)

Question 12

what is octanol (nonpolar solvent)?

Answer 12

water partition coefficient (Kow or P)
-low Kow is a standard method to determine lipophilicity of xenobiotics
-low Kow values >4 indicate high potential for accumulation and toxicity, (ex: organochloride pesticides like DDT)
-“persistent organic pollutants” (POPs)

Question 13

what is simple diffusion of weak organic acids and bases?

Answer 13

are about 75% of all pharmaceuticals and many other xenobiotics such as pesticides and industrial chemicals
-recall: such chemicals exist in both ionized and nonionized forms in solution, and the relative proportion of ionized vs nonionized form depends on the pKa of the xenobiotic and the pH of the solution
-only the nonionized form of the xenobiotic can passively diffuse across cell membranes

Question 14

what are weak organic acids and bases?

Answer 14

-the henderon-hasselbach equation can be used to determine ratio of nonionized vs ionized form of the xenobiotics
-remember that the protonated form of an acid is nonionized (HA) and the protonated form of a base is ionized (BH+)

Question 15

what is the textbook photo of weak organic acids and bases?

Answer 15

Question 16

what is the passive diffusion of a weak acid (pKa=4.4) from stomach (pH=1.4) to bloodstream (pH=7.4)?

Answer 16

Question 17

what is the effect of pH on the ionization of benzioc acid (pKa=4 acid) and aniline (pKa=5 base)?

Answer 17

Question 18

do practice questions on slide 14, 15, 16

Question 19

what is the detailed description of filtration (bulk flow)?

Answer 19

-xenobiotic moves with water through gap junctions between cells due to pressure gradient (ex: blood pressure)
-most cells have gaps of 4nm, most blood vessels (endothelial cells) 2nm, glomerulus 70nm, CNS 0nm
-size of xenobiotic is most important

Question 20

what is the detailed description of facilitated diffusion?

Answer 20

-important for nutrients and electrolytes; certain xenobiotics can compete for these systems
-major families are the organic anion transporters (OATs) and organic cation transporters (OCTs)
-important for excretion

Question 21

what is the detailed description of active transport?

Answer 21

-also important for excretion; brain, liver and kidneys all have active transport systems
-all are “ATP-binding cassette” (ABC proteins); major families are the multi-drug resistance proteins (MDRs and MRPs) and breast cancer resistance protein (BCRP)
-names originated from high expression in certain cancer cells, severely limiting chemotherapeutic treatments
-referred to as “lipophilic vacuum cleaners)

Question 22

what are the four routes of exposure?

Answer 22

-gastrointestinal tract (ingestion)
-inhalation (lung)
-dermal (skin)
-clinical and experimental (intravenous, subcutaneous, intramuscular, intraperitoneal)

Question 23

what is gastrointestinal tract absorption?

Answer 23

-very important route of absorption for many xenobiotics (dietary exposure via food and water)
-most absorption occurs in small intestine due to high surface area

Question 24

what is inhalation absorption?

Answer 24

-important for gases, vapours and particulates

Question 25

what is dermal absorption?

Answer 25

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