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I would like to test a small molecule in a lung disease mouse model.
Should I just rely upon the PK levels of the small molecule in the
plasma (and then assume it is there in the lungs at sufficient levels)
and go ahead with the efficacy model or should I request for lung PK
levels- in order to make sure of the activity of the compound in the
lungs? Is there good correlation between plasma PK levels and lung PK
levels and can it be used as a predictor of lung PK levels? Is there any
variation between the small molecules in terms of plasma to lung
partitioning?
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The following message was posted to: PharmPK
Hi Gururaj_Kalkeri,
Small molecule partitioning into the lung is variable. For example
Voriconazole, a potent
antifungal agent from Pfizer, penetrated well into the pulmonary
epithelial lining fluid
(ELF) in lung transplant patients receiving oral prophylaxis. The ELF
concentrations
exceeded those of the plasma, with an average ELF-to-plasma ratio of
11 (+/-8). However
there is a strong association between plasma and ELF concentrations (r
(2) = 0.95) was
noted. This trend may not be seen similarly with most other agents.
It is good if pk studies are undertaken in both plasma and BAL in
rodent models, as there
are sevaral publications on pk of several drugs done in both plasma
and BAL. That will
give a good estimate how much agent is partitioned in the lungs
during the final stage of
preclinical development.
Ref: Intrapulmonary penetration of voriconazole in patients receiving
an oral
prophylactic regimen.Capitano B, Potoski BA, Husain S, Zhang S,
Paterson DL, Studer SM,
McCurry KR, Venkataramanan R. Antimicrob Agents Chemother. 2006 May;50
(5):1878-80.
Hope this helps.
Thanks
Sripal
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