1 distribution Flashcards
what are compartments? when does distribution happen?
-different locations in body where a xenobiotic is distributed are referred to theoretically as compartments
-initial absorption to “central compartment” (systemic circulation) is followed by distribution to “peripheral compartments” (liver, brain and other organs and tissues)
-thus, after absorption and entry into systemic circulation, there is an immediate rapid distribution throughout body, especially to well-perfused tissues
what are the four main factors that influence distribution?
- blood flow (perfusion): depending on tissue, can range from 3 to 30% of cardiac output
- physiochemical properties of xenobiotic (lipid solubility, pKa, molecular size)
- biding of xenobiotic to plasma proteins and cellular binding proteins
- barriers to distribution
what is plasma protein binding?
-albumin most abundant; xenobiotic have varying affinities for it
-free: bound equilibrium in blood plasma due to reversible binding
-key point: only FREE xenobiotics can diffuse out of bloodstream into tissues because plasma proteins are huge and cannot cross capillary wall
-consider dynamic nature: as free xenobiotic diffuses from blood to tissue, more is released from plasma proteins until tissue sites become saturated. Also as free xenobiotic is excreted, more is released from plasma proteins
what is albumin?
“the bus”
-lots of seats and lots of places for xenobiotics to bind to
-big molecule
-can be saturated
-certain affinities for xenobiotics
what are the tissues involved in tissue protein binding?
-liver and kidney
-adipose tissue
-bone
what is the protein binding of the liver and kidney?
-have high binding capacity for certain xenobiotics
what is the protein binding of adipose tissue?
fat is an important storage depot for highly lipophilic xenobiotics (ex: persistence organic pollutants)
-consider: lean vs obese individuals
-consider: lactation; breast milk is high in fat and can accumulate lipophilic drugs where they can become a route of exposure to neonate
what is the protein binding of bones?
-binds certain xenobiotics (ex: heavy metals such as lead), body cant tell diff between lead and calcium
what are the barriers to distribution?
-blood-brain barrier (BBB)
-placental “barrier”
what is the blood-brain barrier?
-major barrier to many xenobiotics because of tightly joined endothelial cells surrounding CNS and active (ATP-dependent) transporters for removal (ex: MDR, MRP, BCRP)
-consider: not fully developed in embryo and at birth; important toxicological implications
what is the placental “barrier”?
-must assume that any xenobiotic entering maternal circulation is capable of crossing placenta unless proven otherwise
-xenobiotics are tested extensively for their ability to cross placenta and cause teratogenic effects in offspring (recall thalidomide and methylmercury)
what is the definition of volume of distribution?
-the apparent fluid volume in which a xenobiotic appears to be dissolved (how widely a xenobiotic is distributed throughout the body)
-VD is a “proportionality constant” used to compare distribution of xenobiotics, especially pharmaceuticals
what is the volume of distribution (VD)?
xenobiotic dose (mg)/plasma concentration (mg/L)
what is an example of how to calculate volume of distribution?
