Factors Influencing Toxicity Part 2 (for MT2)

Question 1

how does pH alter the ionization of weak acids and bases?

Answer 1

weak acids: become more ionized as pH decreases; weak acids only passively diffuse in an acidic environment (stomach)

weak bases: passively diffuse in a basic environment (intestines)

Question 2

describe bioavailability

Answer 2

the quantity of the toxicant that makes it to circulation, depends on the degree of absorption after first pass metabolism across gut wall (if toxicant delivered IV, bioavailability will be 100%)

Question 3

what does distribution of a toxicant depend on? (6)

Answer 3

1. lipid/water solubility of toxicant
2. serum protein binding: toxicants bind to albumin and alpha glycoproteins; unbound “free” toxicant is active; bound toxicant is not available for clearance and may have short term storage in circulation to be re-released later; this factor is also a concern because for highly protein-bound toxicants when there is a lack of protein as they are now free to do damage
3. presence of specialized barriers
4. degree of organ/tissue perfusion
5. presence/density of receptors/transporters
6. tissue storage

Question 4

describe elimination of toxicants

Answer 4

also called clearance

1. biotransformation/metabolism: occurs in the liver
2. excretion: can occur viral renal (most common), intestinal (bile) fecal, or unabsorbed fecal routes
3. elimination t1/2: the time it takes for plasma concentration to drop by 50%; usually follows first order kinetics, where the fraction of the dose eliminated in a fixed period of time is constant irrespective of the dose BUT exceptions are with hella high doses leading to saturation where the body now follows zero order kinetics and will constantly eliminate that shit out

Question 5

describe renal excretion (3)

Answer 5

1. the primary route of excretion
2. filtration is most common path, is passive, excludes based on size, and only handles unbound toxicants
3. can also do secretion in the proximal tubule; where lipid soluble toxicants follow passive diffusion out or transporters (energy dependent, low capacity) force out

Question 6

describe biliary excretion

Answer 6

species dependent; also depends on polarity and size of the molecule (handles larger molecules than renal)

Question 7

describe renal and biliary reabsorption

Answer 7

in general, reabsorption increases the concentration and toxicity of substances

renal: depends on lipid solubility and urine pH

biliary: allows toxicants to enter enterohepatic circulation, and glucuronide conjugates can convert a substance to a toxic form following reabsorption

Question 8

describe the concept of transporters in toxicokinetics (3)

Answer 8

1. membrane bound proteins that serve as carriers and effect toxicant reabsorption, distribution, and elimination
2. transporters located in the gut, renal proximal tubule, and biliary epithelium act to limit uptake and enhance efflux to clear toxicants
3. also include ATP binding cassette family and soluble carrier protein family