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The following message was posted to: PharmPK
Dear friends,
A question about volume distribution for acidic compounds. To my
understanding, acidic compound usually has small volume distribution,
such
as less than 0.5 L/kg. However, the acidic compound I worked with has
volume
distribution at steady-state (calculated from non-compartmental
model) of 11
L/kg in dog and 0.7L/kg in rat. This compound contains a carboxylic acid
group as well as another basic function group (zwitterion ?) Is there
any
explanation for this ?
Thanks,
Jenny
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The following message was posted to: PharmPK
Jenny,
Besides the basicity/acidity of the compound, the volume of
distribution of drugs are controlled by other physicochemical
properties such as extent of protein binding and partition
coefficient.
Drugs may bind to both the circulating and the stationary proteins
with different consequences: a highly plasma protein bound drug (e.g.,
flurbiprofen and similar drugs) will have a relatively small Vd while
a drug with high tissue protein binding (digoxin) will have a
relatively large Vd. A given drug, however, may have similar extent
of binding to proteins in both sites. In plasma, acidic drugs tend to
bind mainly to albumin while basic compounds have greater affinity
towards alpha acid glycoproteins.
With regards to partition coefficient, unbound drugs (or unbound
fraction of drugs) distribute into the body depending upon their
affinity towards tissues relative to that towards the vascular space.
For example a drug with a high partition coefficient accumulates in
adipose tissues and membranes with a greater extent than does a very
water soluble drug with low partion coefficient.
Therefore, other factors such as these, including acidity/basicity of
a drug need to be taken into account. Hope this helps.
Satjit Brar
Virginia Commonwealth University
Department of Pharmaceutics
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Is the compound distributing differently in the dog compared to the
rat? Have you looked at the blood to plasma ratio in the dog? Maybe
it has affinity for something in the dog compared to the rat.
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Dear Zheng,
Acidic drugs usually have less Vd because of the fact that most of
the acidic ccompounds exists in ionized state in the physiological
fluids (Blood) which has a pH of ~7. However considering individual
candidates, the pKa and the log D (at physiological pH) gives a
qualititative idea about the Vd (Varma et al. Curr. Drug Metab, 2004,
5, 375).
And offcourse the other factors that dictate Vd are the protein
binding, interacting functional groups of the drug.
It may be difficult to explain the observed interspecies. Although
species differences in PK was reported for many drugs it was majorly
attributed to the metabolic differences and the role of GI incase of
orally adm. However, for your reference the below citation showed
drastic differences in Vss between rat Vs Human and dog Vs Human.
Hope it helps.
DRUG METABOLISM AND DISPOSITION, 31:294-305, 2003.
Regards
Varma Manthena
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