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Dear readers,
I am wondering if any body in this forum experienced a situation as below.
We have a compound that shows excellent (greater than 50 %) bioavailability in rat, mouse and dog. In Cyno monkey, however the bioavailabilty was less than 4%. Increasing the PO dose from 1 to 2 mg/kg didn't show any improvement. The compound is soluble and permeable (A to B is 4, but B to A is 28) showing efflux. Normally, we expect rat to show stronger efflux compared to cyno. The in vivo Cl in cyno is not high (less than 20% of hepatic blood flow). Is it possible cyno has an efflux tranporter different or more efficient than rodents? If, so how can we predict what will be the outcome in human? Is there an in vitro system that can predict human and cyno efflux transporter? The formulation used in all species are the same.
I will appreciate your comments, if any of you have experienced a similar situation.
Thomas Nadakal
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The following message was posted to: PharmPK
Hi Thomas,
Did you do a dose proportionality study in monkey. Because, generally if it is a substrate for some transporters, we expect non linear kinetics due to saturation of transporters. How was the metabolic stability in monkey and rat liver microsomes?
Comments from other experts are welcomed.
Thanks
Tausif Ahmed, Ph.D.
DMPK, Sai Advantium Pharma Ltd., Pune
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Dear Thomas
The following papers investigated low oral bioavailability of drugs (mainly as a result of metabolism) in
cynomolgus monkeys which might be useful for you:
Takahashi M, Washio T, Suzuki N, Igeta K and Yamashita S (2009) The species
differences of intestinal drug absorption and first-pass metabolism between
cynomolgus monkeys and humans. J Pharm Sci 98:4343-4353.
Takahashi M, Washio T, Suzuki N, Igeta K and Yamashita S (2010)
Investigation of the Intestinal Permeability and First-Pass Metabolism of
Drugs in Cynomolgus Monkeys Using Single-Pass Intestinal Perfusion.
Biological & Pharmaceutical Bulletin 33:111-116.
Regards
Masoud
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Hello Thomas,
I think there was some differnce in pH in the monkey GI-tract (esp. stomach) did you checked the pH-dependent stability / solubility of your compound ?
Did you recove cmpd from feces afte p.o. dosage ?
kind regards
Dirk
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Thomas,
Do you have IVIVE and the major clearance pathway established for this compound in rat, mouse , dog and monkey and then what does HLM experiment tell you? Metabolism of this compound in monkey intestinal microsomes may also explain poor bioavailability in that species. Even a single species scaling may give you accurate predictions for human PK.
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The following message was posted to: PharmPK
Hello Thomas,
I checked for the pH (ref. RIVM report 623860 010) in monkey. So the pH in stomach is quite high (up to 7-9) and in ceceum and colon lower compared to all other species. Maybe the explanation is in the pka of your compound ?
best regards
Dirk
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Check the report. even under the worst curcumstances, with a bad pylorus, the stomach pH should not get up to 9 (unless someone is getting bicarb or worse). The RIVM reference indicates pH form 2.8 to 4.
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