PCL201H1 Lecture Notes - Lecture 10: Plasma Protein Binding, Glycoprotein, Orosomucoid

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14 Sep 2016
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PCL201
Winter 2014
Lecture 10 Drug Distribution Continued
1. Examine factors that affect the Vd
Protein binding
Tissue binding
Fat reservoirs
Hepatic reservoirs
Disease states
2. Examine the importance of blood flow and the concept of “redistribution”
1. Examine factors that affect the Vd
Protein binding
Binding is reversible, equilibrium between bound and unbound drugs
Only free drugs can leave blood to exert effect or be eliminated
Dissociation constant = Kd = koff/kon = 1/affinity
Increasing [drug] beyond saturation will increase [free drug]
Total drug concentration refers to all drugs in the body, bound & unbound
There are two important plasma proteins for binding
Albumin
most abundant plasma protein
binds weak acids, hormones, and bilirubin
lowered in disease states
Orosomucoid (α-1-acid glycoprotein)
binds weak bases
increased levels during inflammation
Bound drugs may not be eliminated as readily (exception: active transport elimination)
Bound drugs serve as a circulating reservoir, decreased intensity but longer duration
Most important for drugs with low Kd at low [ ]
Can decrease [free drug] decreased effect
Decreased passive elimination
Saturation may occur to increase [free drug]
Drug binding is affected by drug-endogenous compound interactions and drug-drug
interactions
Introducing a more affinitive drug will displace the other drug and increase [free
drug] right after displacement
However, at steady state, [drug] decreases (elimination), fraction free increases,
and other factors are the same
Drug binding is less important in clinical practice as it is in lab theory
Most important for high affinity drugs with narrow T.I.
Tissue binding
Binding to macromolecules (proteins) and accumulate in tissues basis for
pharmacological action if the macromolecule is a receptor or target
Accumulation may be toxic
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