Lecture 3: Excretion

Question 1

Excretion

Answer 1

Toxicants are eliminated from the body by
several routes:
1.Kidney is the most important route (urine)
2.Feces (biliary excretion)
3.Gases (lung)
-Many xenobiotics are biotransformed to more
water-soluble products before they can be
excreted.

Question 2

toxic excretion

Answer 2

Toxic compounds are excreted in the same way that end products of normal metabolism are excreted:

1. Glomerular filtration
2. Tubular secretion
3. Tubular reabsorption

Question 3

Glomerular Filtration

Answer 3

•Kidneys receive about 25% of cardiac output, and ~20% is filtered through the glomeruli (25 g /day of urea is filtered and excreted).
•The glomerular capillaries have very large
pores ( 70 nm) and allow compounds up to a
molecular weight of 60 kDa (<albumin) to be
filtered.
•Passive transport

Question 4

Tubular Secretion

Answer 4

• active transport for acids, bases, neutrals into renal tubules
• Oct: organic cation transporter
• Oat: organic anion transporter
• MDR/Mrp: multidrug resistant transporters

Question 5

Tubular Reabsorption

Answer 5

•Passive: depends on ionization of xenobiotic; lipophilic substances will be reabsorbed from the tubules more than hydrophilic substances.
•under high urinary pH, excretion of acids is increased
•under low urinary pH, excretion of bases is increased
•Active: organic cation transporters (OCT) and peptide transporters
(PEP)

Question 6

Toxicity from Tubular Reabsorption

Answer 6

• Cadmium is reabsorbed as a metallothionine complex through the PEP active transporter.
• Limonene in citrus is reabsorbed in complex with globulin through the PEP transporter.

Question 7

Urine

Answer 7

•Major excretory fluid
•Normal range pH: 4.5-8; normal pH=6.0
Respiratory Alkalosis and Acidosis
↓ CO2 --> ↓ H+ --> ↑ pH alkalosis
↑ CO2 --> ↑ H+ --> ↓ pH acidosis

Question 8

Respiratory acidosis

Answer 8

a. Basis for insult: decreased ventilation → ↑PCO2
-Caused by damage to resp. center; drug CNS depression; obstruction of respiratory passages; breathing excess CO2, neurological damage, pneumonia.
b. Effects & diagnosis: ↑PCO2; ↓pH
c. Immediate compensation: difficult because of primary resp. problem.
d. Slower compensation: renal excretion of H+; production of HCO3-.
e. Long term correction: repair respiratory deficit
f. Excretion:
•Acids/glucuronides, carboxylic acid metabolite classes are excreted less efficiently
•Bases excreted more efficiently.

Question 9

Respiratory alkalosis —less common

Answer 9

a. Basis for insult: hyperventilation → ↓PCO2
-Caused by excessive pulmonary ventilation; excitement; voluntary hyperventilation; high altitude
b. Effects & diagnosis: ↓PCO2; ↑pH
c. Immediate compensation: same problem as respiratory acidosis.
d. Slower compensation: renal excretion of HCO3-
e. Long term correction: repair respiratory deficit
f. Excretion:
•bases excreted less efficiently
•acids excreted more efficiently

Question 10

Metabolic acidosis —

Answer 10

a. Basis for insult: ↑H+ or ↓HCO3-
-Caused by loss of alkali (e.g. diarrhea); failure of kidney to secrete H+
(excretion of HCO3-); formation of excess metabolic acid (e.g., acetoacetate in diabetes); carbonic anhydrase inhibitors; CaCl2 and NH4Cl; high plasma
K+.
b. Effects and diagnosis: ↓pH and ↓HCO3-
c. Immediate compensation: low pH drives respiratory response, effect is to reduce PCO2 and tends to restore HCO3-/CO2 ratio toward 20/1.
d. Long term correction: renal excretion of H+; restoration of HCO3

Question 11

Metabolic alkalosis —

Answer 11

a. Basis for insult: ↓H+ or ↑HCO3-
-Caused by ingestion of alkaline drugs; excessive vomiting; increase Na+ delivery to distal tubule (increases H+ secretion & loss); low plasma K+; excessive aldosterone.
b. Effects and diagnosis: ↑pH and ↑HCO3-
c. Immediate compensation: high pH slows respiratory drive.
-Effect is to accumulate CO2, i.e., elevate PCO2, and restore HCO3-/CO2
toward 20/1
d. Long term correction: renal excretion of excess HCO3-

Question 12

Fecal Excretion

Answer 12

Biliary excretion is the most important source of fecal excretion of xenobiotics and is important for the excretion of their metabolites.

Question 13

Bile Excretion

Answer 13

•Substances with molecular weight of 350-740 are preferentially excreted in bile versus urine, as well as thiol (glutathione) conjugates of mercury, lead, copper.

Question 14

Enterohepatic Circulation

Answer 14

Enterohepatic circulation causes increased retention of xenobiotics conjugated by glucuronic acid because they are deconjugated in the intestine and reabsorbed.

Question 15

Example: Diethylstilbestrol (DES)

Answer 15

• Causes cancer in women.
• Undergoes enterohepatic circulation and is retained in the body by sequential conjugation and deconjugation.
• Phenobarbital increases bile flow and can accelerate excretion of toxins (e.g. -increases excretion of MeHg+).

Question 16

Exhalation

Answer 16

• Substances that exist predominantly in the gas phase at body temperature are eliminated mainly by the lungs.
• The amount of liquid eliminated via the lungs is proportional to its vapor pressure (i.e. breathalizer test to determine ethanol concentration).
• Substances are eliminated via simple diffusion (no transport systems).
• Elimination of gases is roughly inversely proportional to the rate of their absorption (i.e. gases with low solubility in blood, such as
ethylene are rapidly excreted).