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We are aware that if tissue distribution is mediated only by simple
diffusion, the unbound drug concentration in the tissue should be
equal to the unbound drug in plasma when equilibrium is achieved.
Therefore Vdss equals to plasma volume in addition to the sum of each
tissue to plasma partition coefficient multiplied with its respective
However when there is a high bound fraction in tissue compartments
than blood compartment, the total drug concentration in the tissue
will be significantly greater than that in plasma at equilibrium.
Interestingly some of our compounds exhibit significantly higher
levels (> 5-10 folds) in target organs despite of very lower Vdss in
rats. Albeit lower Vdss would be a concern for the compounds that may
act in the central blood compartment for example anti-coagulants, it
may not be so for other classes of compounds.
I would highly appreciate if the members of this forum could explain/
help me on following doubts:
1. Could you provide me the list of drugs of lower Vdss but
significantly higher Tissue to plasma concentration/ partition ratios
2. What could be the reasons for PK/PD disconnect despite of
measuring very high levels of compounds in the target organ other
than being confined to extracellular compartments. But in that case
our standard compound despite of lower target tissue levels exhibit
the activity. How do we justify it?
3. We know that the basic drugs tend to have larger Vdss due to
favorable ion-pair interactions of the basic centers with acidic head
groups of the phospholipids membrane. Does the correlation exist
between physicochemical properties and tissue to plasma partition
coefficient always when the process is not mediated by transporters?
Thanks in advance.
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