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The following message was posted to: PharmPK
Hello,
I would like to ask your opinion about the following study.
A drug, Tacrolimus(Tac) is a substrate of both CYP3A4 and P-gp.
1) when a P-gp inhibitor (say PGPin) was given intravenously with
Tac(IV), BA of
Tac was decreased from 2200 to 1700.
2) when a P-gp and CYP3A4 inhibitor, cyclosporin was given
intravenously with
Tac(IV), BA of Tac was increased from 2200 to 4400.
3) when a CYP3A4 inhibitor (say CYPin) was given iv with Tac (IV), BA
of Tac was
increased from 2200 to 5500.
I understand why BA was increased for case 2 and 3.
However, I have hard time understanding why BA was decreased for case 1.
The researcher was saying that inhibiting P-gp increased CYP3A4
metabolism due
to greater access of the substrate (Drug) to the CYP3A4.
The substrate is exposed to CYP3A4 prior to P-gp because P-gp is
localized on
the exit site (to bile) of hepatocyte (hepatic canaliculi facing the
bile duct
lumen).
I don't understand why inhibiting P-gp decreases BA of the substrate.
the role
of P-gp is pumping the drug into bile, not into blood vessel. And so,
inhibiting P-gp isn't helping drug to be pumping back out to the blood.
I would appreciate your opinion about this issue.
Regards,
Hue.
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might be inhibited reabsorption from intestinum - reducing enterohepatic
circulation might contribute to this effect?
Joachim Boos
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Hi Hue,
While the difference in case #2 and #3 is very large, double of more
the reference value, in the first case the two values are quite
similar.
I would like to suggest to analyze the variability of your data.
I assume these values are averages. It may be possible that the
difference of 500 is not statistically significant and therefore
theP-gp inhibitordid not really affect the pharmacokinetics of
tacrolimus.
radu
Radu D. Pop
Director Biopharmaceutics
Pharma Medica Research Inc.
966 Pantera Drive
Mississauga, Ontario
Canada, L4W 2S1
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The following message was posted to: PharmPK
Hue,
kwonh.aaa.onid.orst.edu wrote:
>
> A drug, Tacrolimus(Tac) is a substrate of both CYP3A4 and P-gp.
> 1) when a P-gp inhibitor (say PGPin) was given intravenously with
> Tac(IV), BA of
> Tac was decreased from 2200 to 1700.
>
> 2) when a P-gp and CYP3A4 inhibitor, cyclosporin was given
> intravenously with
> Tac(IV), BA of Tac was increased from 2200 to 4400.
>
> 3) when a CYP3A4 inhibitor (say CYPin) was given iv with Tac (IV), BA
> of Tac was
> increased from 2200 to 5500.
I find it hard to understand what you mean by BA. If Tac is given IV
then by definition the bioavailability cannot change. Perhaps what was
observed was an increase in Tac AUC reflecting a decrease in Tac
clearance with the PGP inhibitor and the opposite with the CYP3A4
inhibitor. Or are you referring to IV administration of the inhibitors
and oral administration of Tac? If the latter, what does Tac(IV) mean?
> The researcher was saying that inhibiting P-gp increased CYP3A4
> metabolism due to greater access of the substrate (Drug) to the CYP3A4.
> The substrate is exposed to CYP3A4 prior to P-gp because P-gp is
> localized on the exit site (to bile) of hepatocyte (hepatic canaliculi
> facing the
> bile duct lumen).
One of the things that one needs to be careful of is to distinguish
between clearance and changes in pathways of elimination. This quote is
from a review trying to explain increased clearance in women by an
effect on PGP:
"P-glycoprotein efflux can effectively lower the intracellular levels
of a drug and thereby indirectly modulate CYP3A4 metabolism. In women
(who have less P-glycoprotein), one might therefore expect higher
intracellular hepatic levels and consequently greater metabolism and
higher clearance, even though the enzyme protein levels are similar
between men and women."
A decrease in PGP associated efflux in hepatocytes alone may plausibly
increase fractional elimination by CYP3A4 but if anything total
clearance would be *lower* not *higher* with less PGP activity in
women. One would have to postulate a separate mechanism whereby
decreased PGP somehow increases activity of another clearance pathway
(e.g. CYP3A4) in order to conclude that less PGP means higher
clearance. Note that Cummins et al. assert there is no difference in
"enzyme protein levels between men and women" so this additional
mechanism, if it exists, is apparently not due to enzyme concentration.
Cummins CL, Wu CY, Benet LZ. Sex-related differences in the clearance
of cytochrome P450 3A4 substrates may be caused by P-glycoprotein. Clin
Pharmacol Ther 2002;72(5):474-89.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Dear Hue,
This again relates to the same explanation I gave in my earlier
response.
In assessing the combined roles of P-gp and CYP450 on a partcular drug
which
is substrate for both, it is important to understand the relative
specificities of that substrate for P-gp/CYP. Apart from this the
specificity of the inhibitor to inhibit P-gp/CYP is also important.
Generally most of the P-gp or CYP inhibitors have cross specificities.
So,
inhibiton of one would also leads to inhibtion of the other but to a
less
extent.
Coming to your questions:
> 1) when a P-gp inhibitor (say PGPin) was given intravenously with
> Tac(IV), BA of
> Tac was decreased from 2200 to 1700.
My explanation in the earlier response will hold true for this
observation.
> 2) when a P-gp and CYP3A4 inhibitor, cyclosporin was given
> intravenously with
> Tac(IV), BA of Tac was increased from 2200 to 4400.
Becuase inhibting both P-gp and CYP would lead to decreased elimination
of
Tac into bile and decreased metabolism by CYP, leading to huge increase
in
AUC.
> 3) when a CYP3A4 inhibitor (say CYPin) was given iv with Tac (IV), BA
> of Tac was
> increased from 2200 to 5500.
> From the above two observations one could easily understand that Tac
> is a
potent substrate for CYP than for P-gp. That means, CYP has more
limiting
role than P-gp on AUC. That is why inhibting P-gp did not lead to
increase
in Tac AUC (Observarion-1 above) but led to increased metabolism due to
increased residence time in the hepatocyte.
As I mentioned in my earlier response, that this observation is typical
of a
potent CYP substrate with relatively low P-gp affinity.
Hope this helps.
Kasiram.
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Dear Colleagues,
Another point to be considered in this discussion is the possibility
that PGP inhibition affects the exposure of intestinal epithelial cells
to CYP3A inducers. The level of CYP3A expression might well depend on
the presence of a variety of food-derived inducers, whose access to
nuclear receptors is probably regulated by PGP activity. This is
consistent with the observation of Schuetz et al, who reported a clear
influence of diet on the CYP levels of PGP-deficient mice. (Schuetz EG,
Umbenhauer DR, Yasuda K, Brimer C, Nguyen L, Relling MV et al. Altered
expression of hepatic cytochromes P-450 in mice deficient in one or
more mdr1 genes. Mol Pharmacol 2000; 57(1):188-197.)
Hope this helps
Thierry Buclin
Division of clinical Pharmacology & Toxicology
University Hospital of Lausanne - Switzerland
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I have a lot of difficulty accepting what Cummins (and Benet) say about
clearance in their CPT review. Its easy to see that PGP inhibition could
lead to an increase in the fraction of drug that gets metabolized but
this
should not increase the overall clearance and therefore should not
decrease
AUC after an IV dose.
You think it would help you to appreciate that clearance and AUC and
bioavailability (BA) are 3 different things. With an IV dose the AUC is
inversely proportional to clearance and bioavailability is 1 (always).
On
the other hand with oral doses you can see changes in AUC that are due
to
differences in bioavailability and not due to clearance.
Hope this helps.
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)