Dear all,Back to the Top
I have a question for the group. I am not an expert in preclinical pk
and need help in interpreting some results. I am working on a drug that
in isolated human hepatocytes is essentially unmetabolized (99.8%
remains intact after 6 hr incubation). In vivo, 50% of the drug is
excreted by the kidney and renal clearance is 50% total clearance.
Normally I would split total clearance into renal clearance (50%) and
argue that the remaining clearance is hepatic clearance (50%). In this
case, I have split total clearance into renal clearance and non-renal
clearance. Can the argument be made that non-renal clearance is still
hepatic clearance? Are the results from the in vitro experiment of
sufficient validity for non-renal clearance to not be hepatic clearance?
I hope that makes sense.
I appreciate any comments on this matter,
[If you don't see any metabolites (in hepatocytes (or urine?)) it would
seem difficult to assign a value to hepatic clearance. Are there any
other potential routes of excretion? - db]
Hi Peter,Back to the Top
I have seen many examples of this - to the extreme where hepatic
(measured in hepatocytes) is very low, but the compound has low exposure
after i.v. dosing. The answer was in the bile. After completing bile
cannulations over 6 hours I had accounted for 95% of the dosed
parent form, in the bile. If you are observing unchanged compound in the
urine then this is a likely scenario.
The problem is that hepatocytes are indicative of metabolism and, in
isolation, can be used to measure hepatic uptake. However, in vitro
quantification of biliary clearance is hard to come by as it is a
that can be transporter mediated and a broad range of transporters
both the sinusoidal and canalicular membranes of polarised hepatocytes.
mechanism it is the sum of a variety of parts (Y Sugiyama, KS Pang, R
Weisiger, and C Goresky have all published a great deal on these parts).
Simply put there is no clear picture as to what defines a substrate for
biliary clearance or how to measure biliary clearance (as a complete
activity) in vitro.
A more complex model such as the isolated perfused rat liver with bile
collection will illustrate this as compound is stripped from the
and appears unchanged in the bile. I would suggest that this activity
in the liver (to the point where transporter-mediated uptake into the
hepatocyte can be a rate-limiting step prior to metabolism occurring)
Yamazaki,M.; Akiyama,S.; Nishigaki,R.; Sugiyama,Y. (1996) Uptake is the
rate-limiting step in the overall hepatic elimination of pravastatin at
steady-state in rats. Pharm. Res.
Hope this helps,
Pete:Back to the Top
Hepatocytes predicting phase II metabolism is not all that reliable , in
addition you have to account for gut wall metabolism and by non cyp-450
(esterases etc). Therefore though you are justified by saying non-renal
clearance you can not completely rule out hepatic clearance.
St. Louis, MO 63146
Pete,Back to the Top
Can 50% be biliary excretion (still hepatic) of intact parent into the
William,Back to the Top
The answer is yes, I have recently encountered similar issue where 53%
out of 60% fecal elimination was parent after oral dosing (about 93% of
the compound was absorbed). Even after IV dosing, 25% out of 41%
recovered in feces was parent.
Shakil A. Saghir, M.S.P.H., Ph.D., D.A.B.T.
The Dow Chemical Co.
1803 Bldg., Midland, MI 48674
Phone: (989) 636-8708, Fax: (989) 638-9863
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