Back to the Top
Excretion by bile is not a real form of excretion since part of the
compound is always reabsorbed by intestine. This sentence is even
more valid if the compound is not glucuronidated. Is it possible that
a compound could be completely re-absorbed if excreted by bile? What
happens with bile salts? Is it possible that the half life of a drug
excreted by bile and re-absorbed depends only by the percentage of
the drug left un-absorbed and not by metabolism?
For instance, If the intestine absorbs only 0.1 mg of compound and
the bile excretes 1 mg, what happens when the bile excretes 0.1 mg?
The drug will be circulating for ages?
Thank you in advance,
Dr Roberto Conti
Sigma-Tau
Dep. of Endocrinology and Metabolism
00040 pomezia, Roma
Phone: +39-06-91393322
Fax: +39-06-91393988
e-mail. roberto.conti.aaa.sigma-tau.it
Back to the Top
The following message was posted to: PharmPK
Dear Dr. Roberto,
Your question on enterohepatic recycling is quite
interesting. I have made an attempt to answer
partially in a rather lengthy reply !
Anionic xenobiotics (and their glucoronide or sulfate
conjugates), bile salts, cholesterol, and
phospholipids undergo extensive enterohepatic
cycling/enterohepatic circulation (EHC). These
biochemicals are mainly polar (with exceptions), hence
do not enter cell membrane via simple passive
diffusion and require uptake transporters.
The EHC processes i.e., cleavage of conjugates in the
GI lumen and and subsequent re-uptake into intestine
and liver are governed by 2 important factors:
1. microbial flora in the GI
2. transporters involved in uptake, transit and
exit from enterocytes and hepatocyte.
1. Microbial cleavage of glucoronide conjugates is a
prerequisite for release of their parent molecules in
the small intestine, chiefly ileum. Intrinsically, the
microbial load in the GI can vary between healthy
individuals while extrinsically the nature and amount
of GI microbial load is controlled by diet, disease,
or co-adminsitered drugs. Thus, the microbial
population of the GIT is a chief determinant of EHC.
E.g., drug-drug interactions that may arise when
antibiotics are given with drugs that enter the EHC
pathway.
--
2. The intrinsic uptake of unconjuagted bile acids and
xenobiotics into the intestine during EHC primararily
depends on sodium-dependent transporters of the SLC
family.
Na+-dependent bile salt uptake occurs via the
ileal bile salt transporter (ISBT or IBAT), also known
as the apical sodium-dependent bile salt transporter
(ASBT). Both primary and secondary conjugated and
unconjugated bile salts are substrates for ISBT, the
highest affinity being reported for conjugated
dihydroxy bile salts. In contrast to Na-dependent
Taurocholate transporting protein (NTCP), which
transports some nonbile salt substrates and bile salts
from basolateral side of hepatocytes, the substrate
specificity of ISBT appears to be strictly limited to
bile salts. That ISBT is the major intestinal bile
salt uptake system in humans as emphasized by:
a) targeted deletion of ISBT in ileum abrogates EHC
b) ISBT mutations that result in bile salt
malabsorption.
Similarly, the Na+-independent bile salt
transporter Oatp3 transports a range of amphipathic
anions, including bile salts. Oatp3 is found to be
expressed in the brush-border membrane of jejunal
enterocytes.
In addition to uptake systems in the apical
membrane, the apical brush-border membrane also
contains excretory systems, including members of the
Mdr and Mrp family (e.g., Mdr1, Mrp2). As far as bile
salt transport is concerned, Mrp2 could play a role as
an alternative excretory route for
sulfated/glucuronidated bile salts.
Further, a 14-kDa cytosolic intestinal bile
acid-binding protein (I-Babp) that is
cytoplasmatically attached to Isbt represents the most
important protein for transcellular bile salt movement
through enterocytes
An anion exchange mechanism (MRP3) has been
demonstrated at the basolateral membrane of intestinal
cells Mrp3/MRP3 is expressed in the basolateral
membrane in all intestinal segments but is lowest in
duodenum and markedly increased in the terminal ileum
and colon. The high expression of Mrp3/MRP3 in
terminal ileum provides a mechanism to return bile
salts to the portal circulation.
Finally, entry of bile salts and xenobiotics into
the liver occurs via NTCP or members of the anion
transporter family (OATP) while canalicular exit is
controlled by MRP2 and bile salt export protein
(BSEP).
--
The transporters enlisted above are saturable and can
function efficiently only when the concentrations of
the substrates are < Km values (i.e., intrinsic
activity). Higher than Km conentrations of bile acid
or xenobiotics in the GIT or systemic circulation can
saturate the transporters and significantly limit with
the EHC.
Further, many endobiotics as well as other
biochemicals can compete for and/or inhibit these
transporters thereby limiting their access to bile
salts and/or xenobiotics. In addition,the expression
levels of these transporters can be influenced by
diet, disease or drugs. Finally, recent
pharmacogenomics evidence suggests that these
transporters are highly polymorphic leading to
variable expression and function in humans.
The linear and dose-dependent kinetics for a
substrate entering the EHC will be observed only if
the sub-steps, as we know them, were dependent on
passive diffusion-mediated transit of the substrates.
Given the intrinsic and extrinsic factors
mentioned above that may regulate the rate and
magnitude of the EHC processes, it is now apparent
that the overall process will be NON-LINEAR,
NON-PERPETUAL and FINITE. Indeed, the EHC output will
depend on the presence of microbial flora,
transporters and concentrations of substrates
available in the vicinity of transporter
microenvironment.
Perhaps,a great learning example is Estrogen , a known
substrate for glucoronidation (UGT) and sulfation
enzymes (SULT), ISBT, OATP, NTCP and BSEP. EHC of
estrogen-based oral contraceptives has been well
documented.
--
My apologies for the length of the reply. Hope this
helps.
Regards,
Santosh
Back to the Top
The following message was posted to: PharmPK
Dear Santosh,
I have a little question about the EHC terminology. In your answer,
you have
only associated conjugated drugs to EHC. I'd like to know if the term
EHC is
valid in the following case, or if it is strictly reserved to the
case of
conjugated drugs that are cleaved in the GI tract then reabsorbed.
Some drugs which are P-gp substrates and which are well absorbed
(despite
intestinal Pgp) are secreted into bile due to the Pgp present on the
canalicular membrane of hepatocytes. Let's take the case of digoxin :
this
secretion into bile is an important elimination pathway (with renal
secretion) since this molecule has an almost negligible metabolism in
human.
An oral dose of digoxin is given, this dose is absorbed, and part of
this
dose is secreted unchanged into the bile thanks to a Pgp-mediated efflux
process. One can imagine that this unchanged (unconjudated) secreted
amount
will be reabsorbed in the GI tract. This process is very similar to
the one
you described, but without the conjugation/cleavage part. Can we talk in
this case of an enterohepatic cycle, or is this term reserved to
conjugated
drugs? I thought until now that this term could be used in both
cases, but
your explanation casted some doubt on my own definition.
Thanks
Cedric
Back to the Top
The following message was posted to: PharmPK
Ezetimibe, sulindac, and morphine are all subject to enterohepatic
circulation. Significant secondary peaks are observed shortly after
mealtime
with each of these.
Question: are they all conjugated and then converted back to parent
after
secretion into the lumen?
(By the way, GastroPlus(tm) simulates these quite nicely.)
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
Back to the Top
The following message was posted to: PharmPK
Dear Cedric,
Thanks for pointing out the omission.
I agree with you that EHC should include both the
recycling of conjugated and unconjugated species.
For these non-metabolized, unconjugated species their
native physiochemical parameters (Mol.wt,log P etc )
and relevant transporters will play a role in
determining EHC.
Regarding digoxin, it is well known that in humans, it
is non-metabolised and the major pathway of
elimination is renal and governed by GFR. ~90% of
oral dose of digoxin is found in urine. Biliary
excretion, although plausible due to substrate
recognition by influx and efflux transporters such as
P-gp, MRP2 and OATPs, is only minor.
However, it is possible that the PK of other
non-metabolized drugs, if not digoxin, is dependent on
EHC. A comprehensive review (Roberts MS et al.,
Enterohepatic circulation: physiological,
pharmacokinetic and clinical implications. .Clin
Pharmacokinet. 2002;41(10):751-90) addresses this
aspect very nicely.
Dear Walt,
Ezitimibe, Morphine and Sulindac undergo extensive
glucoronidation (and (sulfation) and thence, EHC.
It is interesting to note that since reabsorption of
conjugated or unconjugated species of drugs primarily
occurs in the ileum, EHC provides therapeutic
advantages in the treatment of inflammatory bowel
dieases by increasing half life and delaying
elimination. Indeed, NSAIDs i.e., aminosalicylates
such as sulfasalazine and mesalazine have proven
clinical benefit in this disease and known to undergo
extensive EHC.
Also, recent reports indicate that externally
administered bile acids or derivatives can have
therapeutic benefits in treating intrahepatic
cholestasis for their ability to reduce cholesterol
metabolism and BA overproduction. Medicinal chemists
working in this area have used pharmacokinetic
principles to synthesise bile-acid based drugs that
can preferably enter EHC and thus, have prolonged half
lives. A very good example is
6alpha-ethyl-chenodeoxycholic acid (6-ECDCA) which is
an experimental drug for treatment of intrahepatic
cholestasis.
Hope this helps.
Regards,
Santosh
Back to the Top
Dear Cedric:
It sticks in my mind that Digoxin has significant hepatic
metabolism to the bis and mono digitoxosides, and to the aglycone,
accounting for about 35 % of the elimination. The half-time of
digoxin is about 1.6 days in people with normal renal function, and
about 4.6 days in anuric patients. We used to say that about 34% of
all digoxin was excreted from the body per day, and that this could
be expressed that the percent excretion could be expressed as 14 +
(CCr/5), going from 14% per day in an anuric patient to 34% per day
when CCr = 100, as a rule of thumb. I know it is old, but you might
look at Factors to Consider in Planning Digoxin Therapy. J.Chron.
Dis. 24: 407-416, 1971.
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine,
Division of Geriatric Medicine,
Laboratory of Applied Pharmacokinetics,
USC Keck School of Medicine
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.aaa.usc.edu
Our web site= http://www.lapk.org
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)