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St. John's wort (Hypericum perforatum) is known to significantly decrease
the blood concentrations of the calcineurin inhibitor cyclosporine, thereby
increasing the risk for rejection in patients who have undergone kidney
transplantation.(1-4) As a quick review, several pharmacokinetic studies
have shown that the coadministration of St. John's wort along with cyclosporine
in patients with renal transplantation can result in a reduction in the
concentrations of cyclosporine by 46-52% as compared to baseline.(3,4) More
importantly, this reduction in cyclosporine concentrations required about a
60-65% increase in the daily dose of cyclosporine to compensate for the
increased elimination by St. John's wort.(3,4) To complicate things
further, it appears that the dosage formulation of St. John's wort also has an
impact on the degree of change in cyclosporine concentrations. What is
known is that the increase in cyclosporine elimination appears to be directly
related to the dose or concentration of St. John's wort extract being used.(4,5)
What is St. John's wort doing to cause a reduction in the concentrations of
cyclosporine?
- In order to understand this, a basic review of the metabolic
and elimination pathways for cyclosporine are needed.
- Cyclosporine's
metabolism is dependent on the presence and function of the cytochrome P450
(CYP) 3A4 enzyme, which means cyclosporine is a substrate CYP3A4.(6,7)
- Furthermore, cyclosporine's elimination from cells and ultimately from the body
is partially mediated by P-glycoprotein (Pgp), which makes it also a substrate
for Pgp.(8,9)
- These two pathways of clearance are important to
understanding why St. John's wort causes cyclosporine concentrations to
decrease.
- For purposes of being complete, cyclosporine is a also a potent
inhibitor of several influx cell membrane transporters (OATP1B1, OATP1B3,
OATP2B1) as well as the efflux cell membrane transporters (MRP2 and P-gp).(8,10)
As such, it is evident why drug-drug interactions between cyclosporine and
other medications are not only complex, but cannot be easily or fully explained
by the a simple comparison of the CYP450 enzyme pathways between two or more
medications.
How does St. John's wort influence CYP3A4 and Pgp activity which is known to reduce
cyclosporine concentrations?
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St. John's wort is a substrate for the activation of the
pregnane X receptor (PXR), which is a well known nuclear receptor found in the
cytoplasm of various cells, including liver and gastrointestinal cells.(11,12)
- The PXR is important because it is one of the transcription factors known to
influence gene expression of both CYP3A4 and Pgp within the nucleus of hepatic
and intestinal cells.(12,13)
- Therefore, any substrate that activates PXR will also
increase the gene expression of CYP3A4, which will make more CYP3A4 enzyme
available to metabolize more cyclosporine and increase the expression of Pgp,
which will increase the presence of Pgp mediated efflux of cyclosporine.
How does St. John's wort actually increase the gene transcription of both CYP3A4
and Pgp inside the cell?
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St.
John's wort is an herb that is derived from the tops of the flowering parts
of Hypericum perforatum L. and is known to have several active
ingredients which include cyclopseudohypericin, hypericin, hyperforin,
isohypericin, protohypericin, pseudohypericin and several other flavonoids.(14)
As it relates to these ingredients, hyperforin specially is a substrate, or
activator, of PXR.(11)
- As mentioned before, PXR is a nuclear receptor found
in the cytoplasm of cells. It has 3 major domains that influence its
function and level of activity on gene expression. The first domain,
(activation function 1 (AF-1) domain) located at the amino terminus, is where
recognition of other transcription factors and/or co-activators cause
ligand-independent activation. The second domain (DNA-binding domain) is
the part that directly binds to DNA to modulate gene transcription. The third
domain (ligand-binding domain) on PXR is where substrates, like drugs, bind to
"activate" the transcription of more genes.
- Therefore, as St John's
wort passes through the cell membrane, by diffusion or transport, it will bind
to the ligand-binding domain of PXR in the cytoplasm. This causes a
dissociation of the histone deacetylase-containing complex (transcriptions
co-repressors) so that PXR can then enter the nucleus. Once in the
nucleus of the cell, the ligand-receptor complex either recruits co-activators
to form a homodimer or heterodimer with the retinoid X receptor (RXR), where it
can now bind to response elements in the promoter and enhancer regions of the
target gene. Once this occurs, gene transcription for CYP3A4 is turned on
as well as activation of the ABCB1gene, which is needed to make
Pgp.
- The more CYP3A4 and Pgp transcribed, the greater the ability to
metabolize medications known to be a substrate for CYP3A4 and eliminate
substrates of Pgp from inside the cell, thereby accelerating their clearance
from the body.
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