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Dear PharmPK experts,
In a mouse PK study with IV and PO administration, drug concentration levels in plasma were
unexpectedly low (Cmax = 10.9 ng/mL, AUClast = 13.5 ng*hr/mL, BA = 1.41%).
The drug compound didn’t have any metabolic stability issue and IVIVC through liver microsomal
stability was pretty tight (suggesting no specific efflux transporter effect).
Currently we’re investigating RBC uptake to confirm red blood cell binding, but I slightly doubt
this effect on this PK study because data from IV didn’t seem to be not related to RBC
(Co = 365 ng/mL, AUClast = 192 ng*hr/mL)
Is there any possibility I missed to interpretate PK data which have low drug concentration only in
PO administration?
Please suggest any approach or give any comment to understand this type of PK profile.
Thanks!
Sujin
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Sujin,
Do you have any information regarding absorption?
Best regards,
Walt
Walt Woltosz
Chairman and CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534
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[A few replies while I slept :-) db]
Hi sujin, why don't you analyse in lines of solubility and permeability?. If both are low then the
answer lies there.
Thanks and regards
Jitendar Reddy
Jitendar Reddy
--
Hi Walt,
For absorption, detection for drug concentration was only available after 0.25 hr (no exposure at
0.083 hr as first time point).
Tmax is 1 hr and Tlast is 2 hr.
Is it helpful information you can use?
Sujin
Sujin Ahn, Ph.D.
Team Leader, DMPK
Institut Pasteur Korea
696 Sampyeong-dong, Bundang-gu
Seongnam-si, Gyeonggi-do, 463-400 Korea
Sujin AHN
--
Any additional information about
Solubility in water
LogP and LogD
Molecular Wright?
Best regards
Srefano
Stefano Porzio
--
Hi Sujin,
What is the solubility of the compound at different pH from 2 (stomach) to 7 (lower GI tract) in
buffer?
Was the formulation used for the IV and oral routes the same?
You could consider repeating the experiment in rats and if you still have F=1.4% but when
administering the compound in solution through the portal vein bioavailability increases, you might
have a solubility/degradation issue somewhere in the GI tract.
Alternatively you might have metabolism in the gut wall which express various Phase I and II
metabolism enzymes. To test this you could incubate your compound with intestinal microsomes
however, it is unlikely that the results will be much different from what you have seen using liver
microsomes as the overall metabolic activity in the gut is lower than that in the liver as not all,
the CYPs are expressed in the gut.
See for details: Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In
Vitro Clearance and Permeability Data. Drug Metab. Dispos. 2010 38(7): 1147-1158.
Best
Stefano
--
STEFANO PERSIANI, Ph.D.
Director
Translational Sciences and Pharmacokinetics Department
ROTTAPHARM BIOTECH
Rottapharm Biotech S.r.l.
Via Valosa di Sopra, 9
20900 Monza - ITALY
Persiani Stefano
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You could try getting info from ACD labs ILAB
Edward O'Connor
--
Hi Sujin
Have you checked UGTmediated Phase II metabolism of the compound ?
Murari Pal
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