DISCUSSION
Senna (Cassia senna) is commonly used as a laxative in different
herbal-based medicines. Both its leaves and pods contain active
ingredients of an anthraquinone nature, mainly Sennosides A and
Sennosides B (hydroxyanthracene heterosides). These undergo bacterial
hydrolysis and subsequent metabolic reduction in the large intestine,
where they are converted into active metabolites in the form of rhein
anthrone (1). It is classified as a contact or stimulant laxative; its
activity is based on two different mechanisms of action. On the one
hand, by direct stimulation of the nerve plexus in the large intestine
mucosa, which increases peristalsis. On the other hand, it modifies
fluids and electrolytes absorption in the colon, and appears to have a
secretory effect (1).
In the large intestine, in vitro models have shown that sennoside
metabolites undergo a significant secretory activity, probably mediated
by efflux pumps (2), which limits its passage into the plasmatic
circulation. The vast majority of sennosides are excreted via the feces
(approximately 90%), and the metabolites that reach plasma circulation
are excreted via the kidneys and bile. Cytochrome-mediated hepatic
metabolism has not been described. There are few described interactions
between Senna and drugs, most of them related to electrolyte
disturbances due to concomitant use with other laxatives or due to
increased intestinal transit that may limit the absorption of drugs with
low bioavailability (3, 4).
Tacrolimus is an anticalcineurin drug, with a narrow therapeutic index,
used as an immunosuppressant in the prophylaxis and treatment of renal,
hepatic, and cardiac graft rejection. Tacrolimus is metabolised mainly
through CYP3A4 and CYP3A5 in the liver and intestine and to a lesser
extent by CYP2C19. Mainly in the intestine, tacrolimus is a substrate
for efflux pumps such as P-glycoprotein (P-gp) (4). Several interactions
between tacrolimus and various phytotherapeutic compounds have been
described. Those that are inducers of CYP3A4 and P-gp (e.g.,Hypericum perforatum ) have been shown to significantly reduce
considerably the plasma concentrations of tacrolimus. Whereas those that
act by inhibiting CYP3A4 and P-gp (e.g., Citrus paradisi or Citrus
grandis ”grapefruit juice”, Curcuma longa, etc.) increase the
plasma concentrations of the immunosuppressant (5). Previous studies
have shown P-gp substrate concentration-dependent saturation with
cyclosporine (6) or taxanes (7). Although the P-gp inducers have not
shown relevant effects, its inhibition or saturation, as hypothesized in
this case, could be clinically relevant (8). Administration of a single
dose of verapamil (potent P-gp inhibitor) one hour before or
concomitantly with dabigatran exilate (P-gp substrates drugs not related
to CYP metabolism) increased AUC 2.4-fold and 2.1-fold respectively (9).
Concomitant administration of two substrates may saturate the efflux
pumps, increasing the exposure to both drugs. The administration of the
immediate or extended-release tacrolimus formulations, which reach their
Cmax between 1-3h, makes the interaction more likely. The clinical
impact of the interaction is based on the saturation of the efflux pumps
in the absorption phase of tacrolimus, reducing its expulsion into the
intestinal lumen before entering to plasmatic circulation.
Although the percentage of Glycyrrhiza glabra and Mentha piperitapresent in the herbal preparation is negligible compared to that of
Cassia, the potential interactions with tacrolimus that could have
clinical relevance were revised.
Glycyrrhiza glabra ,
traditionally known as a specie of licorice, is a plant of theFabaceae family, whose roots are used as a traditional remedy in
the treatment of dyspepsia and peptic ulcers. It is important to
differentiate the species of licorice because there are substantial
differences in its constituents and their interaction profile varies.
Although there are discrepancies, recent data suggest that it acts as a
weak inhibitor of CYP3A4 and CYP2C19 (10, 11), probably without clinical
relevance. In addition, Glycyrrhiza glabra acts as an inhibitor
of P-gp, causing an increase in the intracellular concentration of
daunorubicin, which is a substrate of P-gp (12), unlikeGlycyrrhiza uralensis whose major component glycyrrhizin has
shown the opposite effect (13). Regarding the other component of the
herbal preparation, the leaves of Mentha piperita traditionally
known as peppermint (a plant of the Labiateae family) have been
traditionally used for digestive disorders as a spasmolytic, antiemetic
and sedative. In vitro studies suggest a weak inhibitor effect on the
metabolism mediated by CYP3A4 and a stronger one on that mediated by
CYP2C19 (14, 15).
In this case, we suggest that the sennosides act by saturating the
efflux pumps, reducing the excretion of tacrolimus, which decreases its
clearance by 80% when administered at the same time. We observed a
2.8-fold increase in their plasma concentration and a 2.1-fold increase
in AUC. A metabolism interaction by Glycyrrhiza glabra orMentha piperita is unlikely to have a clinical impact due to
their low proportion in the herbal preparation and their interaction
profile, but we cannot rule it out due to the significant increase in
exposure. The rapid recovery of clearance after the suspension of the
herbal preparation suggests that it is not an enzymatic inhibition.
Further studies are needed to analyze the relationship between efflux
pumps and sennosides.
AUTHOR CONTRIBUTION:
BP and MS interpreted data. BP, MS, DG, NM, RL wrote the original draft.
BP and MS performed the pharmacokinetic analysis. All authors revised
the manuscript. All authors approved the final version of the
manuscript.
FUNDING:
This report received no special funding.
COMPETING INTERESTS:
The authors have no conflicts of interest to declare.
ETHICAL APPROVAL:
Not applicable.
DATA AVAILABILITY STATEMENT:
Additional data are available from the corresponding author upon
reasonable request.
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