Back to the Top
Dear group:
My entry into the field of PK is recent and there are a couple of PK
concepts that I am not able to understand from PK books etc and I
would really appreciate it if somebody can either provide me with
some clarification or guide me to an easy to read resource.
When looking at the clearances of a compound, how does one decide
whether it is high or low ? Are there any upper and lower limits one
can refer to ? Are there any such numbers with respect to total body
clearance ? Can one interpret total clearance as high or low when F
is not known ? In relation to this, when one reads the term: high
clearance drug or low clearance drug, is this information related to
total clearance or to the hepatic clearance of the compound - what is
the basis of such a discretion (any magic numbers ?) ?
Would it be correct to classify a drug with renal clearance above 120
mL/min as a high renal clearance drug (based on CrCL I assume ?).
Thank you in advance for any help.
Best regards
David
Back to the Top
The following message was posted to: PharmPK
David,
In answer to your questions, here are some brief responses.
Question. When looking at the clearances of a compound, how does one
decide
whether it is high or low ?
Response. Total (blood) clearance (CL) can be compared to hepatic
blood flow
(QH). The hepatic extraction ratio (EH) can be calculated as CL/QH (a
fraction with an upper limit of 1). EH values approaching 1 may be
considered to be high and approaching zero, low.
Question. Are there any upper and lower limits one can refer to ?
Response. Some texts state that EH values <0.3 are low and >0.7 are
high,
but this isn't especially helpful.
Question. Can one interpret total clearance as high or low when F is not
known ?
Response. Perhaps this question should be looked at another way. If F
is not
known, and given drug is predominantly metabolised by the liver, an
estimate
of maximum oral bioavailability is given by F = 1-EH.
Question. In relation to this, when one reads the term: high
clearance drug
or low clearance drug, is this information related to total clearance
or to
the hepatic clearance of the compound - what is the basis of such a
discretion.
Response. My previous responses should cover this question; i.e. CL is
related to hepatic blood flow, assuming predominant hepatic metabolism.
Total CL is sum of all clearances (hepatic, renal and any other)
Question. Would it be correct to classify a drug with renal clearance
above
120 mL/min as a high renal clearance drug (based on CrCL I assume ?).
Response. Unbound renal clearance (CLRu) can be compared to glomerular
filtration rate (GFR). Values of CLRu >GFR suggest net renal tubular
secretion. Values of CLRureabsorption. CLRu
can be compared to CrCL to assess affect of renal function on renal
clearance.
Best Regards,
Charlie
KinetAssist Limited
Consultant
Larchwood
Shieldhill Road
Quothquan
Lanarks
ML126NA
Charlie.brindley.at.kinetassist.com
Back to the Top
The following message was posted to: PharmPK
Hi David and Charlie
Please consider these thoughts. The concept of total (systemic or
plasma) clearance (CL) refers to the ensemble of all possible
processes responsible for the clearing of the drug from the body,
usually replaced by the notion of blood stream. A better definition
uses the fraction of the volume of distribution cleared of drug per
unit time. Anyway, for practical purposes the interpretation about
the magnitude of total clearance should use the cardiac output as a
yardstick, normally about 30L/min in adults, and what fraction of it
corresponds to the CL, assuming homogeneous disposition. When needed,
partitions of this concept are made such as renal versus nonrenal (or
metabolic) CL, or all the way considering renal, hepatic, pulmonary,
dermal, intestinal, ... , CL's as required. In doing this, the sum of
all the parts adds up to the total CL revealing the magnitude of each
component. Let's say if 90% of the total CL takes place by the renal
route, then the nonrenal pathway has lower magnitude. However, the
concept of extraction ratio (ER), which applies to every clearing
process, conveys a different type of information. While the CL refers
to the efficacy of the clearing process, the ER relates to its
efficiency. It's similar to saying that we can control the
temperature of a room efficaciously, but more or less efficiently. So
a small CL value may correspond to a small of large ER. In the
hepatic CL case, the upper limit may be considered to be the (portal,
not arterial) blood flow. But hepatic CL may overall account only for
let's say 10% of the total CL and still correspond to a hepatic ER of
99%, meaning that the hepatic clearing process is very efficient, it
takes perhaps just one 'passage' through the liver, although not that
relevant overall. Conversely, the metabolic pathway may be the most
relevant (f_metab=0.9, the drug is not cleared appreciably any other
way) but if ER_metab% that means the process has limited efficiency,
it will require multiple 'passages' or a larger dwelling time. So I
always keep CL and ER separate as far as interpreting them.
About the bioavailability (BA) issue, we should distinguish relative
or pharmaceutical BA from absolute or presystemic BA. About the
former, drug that was not absorbed cannot later on be cleared (see
the archives for discussions about CL and CL/F, just a ratio between
two unknowns). But about the latter, it is usual to attribute it to a
significant first passage through the liver and thus the relationship
F'=1-ER. Careful with intestinal Pgp efflux, intestinal bacterial
metabolism, stability issues, among other non-hepatic processes,
which obviously are implicated in the BA but may not correspond to a
clearance term (some authors use different notations for F' and F).
Finally, the renal CL interpretation in comparison with the GFR
should consider the 3 cases Charlie mentioned inferring about
filtration, secretion and reabsorption, separate from the relative
magnitude of renal CL with respect to the total CL. I just recommend
a keen peek at Jelliffe's work about serum creatinine versus creat.CL
and the many considerations thereof when interpreting renal CL.
All the best
Luis
--
Luis M. Pereira, Ph.D.
Assistant Professor, Biopharmaceutics and Pharmacokinetics
Massachusetts College of Pharmacy and Health Sciences
179 Longwood Ave, Boston, MA 02115
Phone: (617) 732-2905
Fax: (617) 732-2228
Luis.Pereira.-at-.bos.mcphs.edu
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Clearance" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)