Distribution

Question 1

What are compartments

Answer 1

Different locations in the body where a xenobiotic is distributed

Question 2

Which compartment is where initial absorption

Answer 2

Central compartment (systemic circulation)

Question 3

which compartment follows after initial absorption

Answer 3

distribution to peripheral compartments ie liver, brain, other organs and tissues

Question 4

After absorption how fast does distribution occur

Answer 4

after entry into the systemic circulation, immediate and rapid distribution occurs throughout body, especially to well-perfused tissues

Question 5

What are the four major factors influencing distribution

Answer 5

1. Blood flow (perfusion) - 3-30% cardiac output
2. physicochemical properties of xenobiotic (lipid solubility, pka, molecular size)
3. Binding of xenobiotic to plasma proteins and cellular binding proteins
4. Barriers to distribution - protects the CNS

Question 6

Which plasma protein is the most abundant

Answer 6

Albumin

Question 7

Only FREE xenobiotic can diffuse out of bloodstream into tissues, why?

Answer 7

Because plasma proteins are huge and cannot cross capillary walls

Question 8

albumin the bus

Answer 8

lots of seats, very abundant, little docking sites

Question 9

Which two organs have high binding capacities for certain xenobiotics

Answer 9

Liver and kidney

Question 9

bone binds certain xenobiotics such as what?

Answer 9

Heavy metals such as leadA

Question 10

why is adipose tissue (Fat) important

Answer 10

Adipose tissue is an important storage depot for highly lipophilic xenobiotics
- consider lean vs obese individuals
- consider lacation; breast milk is high in fat and can accumulate lipophilic drugs, where they can become a route of exposure to neonate

Question 11

What is BBB

Answer 11

Blood Brain Barrier, major barrier to many xenobiotics because of tightly joined endothelial cells surrounding CNS and active transporters for removal

Question 12

placental barrier

Answer 12

must assume that any xenobiotic entering meternal circulation is capable of crossing placenta unless proven otherwise

Question 13

xenobiotics are tested extensively for the ability to cross placenta and cause teratogenic effects in offspring (recall thalidomide and methylmercury)

Question 14

Volume of Distribution (VD)

Answer 14

The apparent fluid volume in which a xenobiotic appears to be dissolved (how widely a xenobiotic is distributed throughout the body)
is proportionally constant - used to compare distribution of xenobiotics, especially pharmaceuticals

Question 15

What is the equation for Vd

Answer 15

Vd = total xenobiotic dose (mg) / plasma xenobiotic concentration (mg/L)

Question 16

what does high Vd mean what does low Vd mean

Answer 16

high vd means extensive distrubution of xenobiotic and high affinity for tissues
low vd means xenobiotic is restricted mainly to blood plasma, mainly due to high plasma protein binding

Question 17

Vd example question
Xenobiotic A: 1000 mg dose administered intravenously, plasma concentration at equilibrium (about 15 min after injection) is 1 mg/L

Answer 17

Vd = total xenobiotic dose (mg)/plasma xenobiotic conc (mg/L)
Vd = 1000mg /1mg/L = 1000 L
Thus xenobiotic A has a high Vd and is likely lipophilic with low plasma protein binding affinity

Question 18

Xenobiotic B:
1000 mg dose administered intravenously, plasma concentration at equilibrium (about 15 min after injection) is 100 mg/L

Answer 18

vd = total xenobiotic dose (mg)/plasma xenobiotic concentration (mg/L)
Vd= 1000mg/ 100 mg/L = 10 L
Thus xenobiotic B has a low Vd and likely has high plasma protein binding affinity