Deck 13: Routes of Administration and Which Organs Are Most Likely Impacted Based on Route and Toxicokinetic Models

Question 1

Explain the skin absorption equation Ks = k_e x M[1-exp(-k_ex t)].

Answer 1

The amount remaining in the body (M) the elimination rate (k_e) are the major factors that depend on time (t). The more hydrophobic the compound the higher the skin absorption will be such as methyl benzene (toluene) as compared with alcohols that are more hydrophilic. The Kp or permeation coefficient is calculated by dividing the Ks with the concentration of the chemical in the solvent mixture.

Question 2

What are the models for small-molecular-weight absorption, high-molecular-weight absorption and protein absorption by the ocular route?

Answer 2

The highly hydrated eye absorbs acetaminophen as a low molecular weight compound, 120 kDa dextran as a high molecular weight chemical, and insulin as its model protein. There are important species differences in the thickness of the sclera (larger in pig and similar in rabbit) that alter the absorption profile. However, the rabbit eye is not a good model for absorption of a gellan gum formation of technetium-99m labeled diethylenetriaminepentaacetic acid compared to the same compound in isotonic saline, as the human retains the gum formation better.

Question 3

Why is the AUC rather than the concentration at one time point by oral administration used to calculate bioavailability?

Answer 3

The initial concentration may be the same for a young adult human versus an elderly person with poor kidney function if their body composition is similar. However, the AUC will vary greatly. Similarly, an infant has less barriers to absorption and may have much higher concentrations from a similar dosage. Therefore the (oral) bioavailability is the area under the curve from time 0 to infinity (until eliminated) x 100 (for percent) divided by the area under the curve for the intravenous route where the concentration is highest at time 0 and all the compound is definitely internal. The oral route should have a lag time before absorption takes place and digestion or charge and carriers will make a decided difference in absorption as will damage to the intestinal lining.

Question 4

What factors do the National Toxicology Program recommend to be included in a toxicokinetic study?

Question 5

What is enterohepatic recirculation and how does it complicate modeling?

Question 6

What is the problem with using the rat as a model of acetochlor or similar compound inhalation toxicity?

Question 7

Why doesn't paraquat have to be inhaled to damage the lung?

Question 8

Why might a water soluble toxicant be as toxic via intravenous exposure as intramuscular or subcutaneous exposure while a hydrophobic toxicant may be initially less toxic via the nonvascular routes? What would the intraperitoneal route indicate?