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Hello Guys!
I was wondering if anyone can shed some light on the presence of drug
metabolizing enzyme in the lungs. The drug in question is a plant
polyphenol that has minimal oral bioavalability. It undergoes
extensive first pass metabolism in the small intestine and gets
glucuronidated in the liver. However, I was wondering if the drug is
developed for pulmonary delivery, can its metabolism be averted?
BUT, the major concern is whether lungs can effectively metabolize
the drug as well. Although, I am assuming here that glucuronidation
occurs primarily in the liver, but I wanted to know whether the
possibility of it getting transformed in the lungs exist.
Any ideas are welcome!
Thanks so much!!
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The following message was posted to: PharmPK
The lungs are documented as having P-450s.
In general there are fewer isozymes than in the liver and they may be at
a lower concentration (specific content). So if the forms responsible
for liver and intestinal metabolism are absent in the lung there is a
good chance for a favorable bioavailability.
Note - This does not include allowance for induction of the lung P-450s
which is possible (by xenobiotics and endogenous factors) so metabolism
can be altered over time.
Regards,
Karsten Holm,
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The following message was posted to: PharmPK
Hello
Human lung has drug metabolising capacity by both phase I and II enzymes
(please see a recent review article)
Zhang JY, Wang Y, Prakash C. Xenobiotic-metabolizing enzymes in human
lung.
Curr Drug Metab. 2006 Dec;7(8):939-48.
Also remember that a large fraction of any drug administered by
inhalation
(50% or so) is swollen and undergoes first pass elimination similar
to oral
dosage forms.
Hope it helps
Fatemeh Akhlaghi, PharmD, PhD
Associate Professor in Pharmacokinetics
Biomedical and Pharmaceutical Sciences (BPS)
University of Rhode Island
125 Fogarty Hall, 41 Lower College Road
Kingston, RI 02881, USA
Phone/Fax: (401) 874 9205/(401) 874 2181
Email: fatemeh.at.uri.edu
Laboratory Website: http://www.uri.edu/pharmacy/faculty/aps/akhlaghi/
index
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Dear Sun and Shine,
The lung certainly has metabolic capacity. One way to check if your
compound is so affected is the perfused, respiring, isolated lung.
It is important to check metabolism by all 3 routes of delivery to
the lung: via the airways, the pulmonary artery and the bronchial
artery.
Ian Smith
ConsultantToxicologist
ASIS Solutions
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The review articles posted earlier are a great resource. Have you
conducted a CYP450 isotyping in hepatic microsomes and in vitro
glucuronidation potential in hepatocytes to determine where and under
what conditions your drug has metabolic liabilities. Also consider
purchasing lung microsomes and running metabolic stability studies
under those conditions. An alternate for your drug maybe a nasal
spray, nasal insufflation methodology with formulation enhancement
for gel forming. This will avoid certain "first pass" reductions in
exposure you may be encountering. There are a number of nasal
steroids that have been successfully formulated to not become oral
doses following and intranasal dose.
Sanjeev Thohan, PhD
Director, DMPK
Exelixis, Inc
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