Back to the Top
Hi all,
Need your valuable inputs in concluding one of my PK study. I have investigated oral
pharmacokinetics of a drug in late pregnant (LPR) and non-pregnant rats (NPR) and have seen
pregnancy-specific alterations in plasma pharmacokinetics such as high clearance, decreased
exposures, higher metabolism (liver microsomes) etc. I also measured the CSF levels of the drug in
late pregnant and non-pregnant rats in the same animals. I need your inputs to know if I am
interpreting the CSF data correctly.
FYI, Drug PK profile is
1. PPB-80% (Which remained fairly similar in plasma of LPR and NPR), drug is primarily bound to
albumin
2. In vitro met stab is significantly lower in LPR than NPR, drug is predominantly metabolized by
UTP1A2 which is known to be up-regulated during pregnancy
3. Lower Cmax and AUC and higher CL in LPR than NPR
4. But CSF PK profile remained fairly similar in LPR and NPR in spite of low plasma levels in LPR.
Drug CSF profile is known to follow plasma profile (literature data). To understand this disconnect
and to know if similar CSF PK is the result of increased BBB permeability in LPR or something else,
I did an i.v. study in LPR and NPR.
5. Following i.v. dose, CSF and plasma was collected at 2, 5 and 10 min post dose and drug showed
significantly higher CSF to plasma ratio in LPR than NPR.
In the light of i.v. CSF/Plasma data, is it fair enough to assume/attribute/conclude that the higher
CSF/Plasma ratio is due to higher BBB permeability in LPR than NPR? Is there any definitive or
direct study to further substantiate this conclusion?
Awaiting your valuable inputs.
Best,
Young
Back to the Top
Hi Young
Very interesting study!
Are these single dose studies, or is this chronic dosing such that you expect to be at steady state?
So, when you calculate the volume of distribution following IV doses, is that different between
pregnant and non pregnant rats? What happens to Tmax in the pregnant vs non pregnant rats?
Also, some thoughts on up regulated metabolism:
-Do you know the metabolic pathway for your compound other than UTP1A2? Can you break it down by
isoform?
-could you prepare liver microsomes from both groups of animals and check for differences in
functional assays with probe substrates? Alternatively, could you dose the live rats with probe
substrates and look for differences in metabolism?
- mRNA, western blot for message and protein expression changes between groups?
-Also, don't forget that the placenta is an organ with it's own transporters and metabolism.
As for the BBB question,
Have you thought of adding in a Pgp inhibitor and seeing what happens?
Could you possibly repeat the experiment in MDR1 knock out animals (mice)? Depending upon your
budget and specific interest :)
Good luck with your work, I look forward to hearing other people's ideas.
Rachel
Back to the Top
Hi,
Several techniques including the brain perfusion method were designed to measure BBB permeability of
drug under various conditions. You may want to check:
Nicolazzo JA, Charman SA, Charman WN. (2006) Methods to assess drug permeability across the
blood-brain barrier. J Pharm Pharmacol. 2006 Mar;58(3):281-93. Review.
Smith QR (1996) Brain perfusion systems for studies of drug uptake and metabolism in the central
nervous system. In: Models for assessing drug absorption and metabolism, vol 8 (Borchardt RT, Smith
PL, Wilson G, eds), New York: Plenum Press, pp 285–30
Takasato Y, Rapoport SI, Smith QR (1984) An in situ brain perfusion technique to study
cerebrovascular transport in the rat. Am J Physiol 247:H484–H493
Sebastien
Back to the Top
The blood/plasma/csf barrier is different from the blood brain barrier, yet you seem to link them as
the same. The embryo/fetus enjoys numerous advantages which dispose it to be superior to the host
in competitions for numerous nutrients (O2, sugars). Perhaps you are running up against this and
hormonal mediated changes in the BBB, blood csf barriers( choroid) and csf blood and brain barriers
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@lists.ucdenver.edu with "Pregnancy and BBB permeability" as the subject |
Copyright 1995-2014 David W. A. Bourne (david@boomer.org)