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The following message was posted to: PharmPK
Hello all,
My question pertains to renally eliminated drugs and I'll explain it
hypothetically:
Say a drug is almost entirely renally eliminated and is known to undergo
active tubular secretion (CLr is approximately 3-fold higher than GFR);
it can be assumed reabsorption is negligible. The drug disposition can
be described by a one-compartment model and there is no evidence of
non-linear kinetics (in the given dose range). Protein binding is low
(<20%) and the extraction ratio, ER, is also low (~25%).
For a group of subjects exhibiting the same creatinine clearance, a
number of individuals show a considerably higher elimination rate
constant, Ke. What are possible explanations for this occurrence? Can
this difference simply be explained by a change in volume of
distribution, in light of the low plasma protein binding and the drug's
hydropilicity? For drugs with low ERs, the elimination is affected by
protein binding - but isn't this relationship more predominant in highly
plasma protein-bound drugs? Assuming Vd is relatively similar for all
individuals (and metabolism not being a significant factor), are there
other possibilities for this difference? Does the specific process of
active renal secretion show very large inter-individual differences
(keeping all other kidney functioning constant, omitting protein-binding
effects, and the presence of competing concomitant medications) or is it
altered in any way by age, non-renal disease, etc.?
Sincerely,
David Jaworowicz
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)