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Hello,
I would like to know when accessing compound from Vd and Cl stand
point, is there a certain number like if Vd(obs) in mL/kg greater
than 400 is considered for a compound to be in plasma and not in
other tissues. Is there a number with clearance value also? Please
include units. Any reference or information from your experience will
be helpful.
Thank you
Anila
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Dear Anila,
Thank you for an interesting question. Low Vd (.-at-.8L) will reflect a
high degree of plasma protein binding. Medium Vd (30L) represents
distribution in total body water and on. I will be happy to discuss
in detail with you if you let me know how I can reach you. Please
feel free to contact me directly at this email address.
Best regards,
Sue
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Dear Anila:
The apparent volume of distribution is the theoretical volume of
fluid into which the total drug administered would have to be diluted
to produce the concentration in plasma, for example, if 1000 mg of a
drug is given and the subsequent plasma concentration is 10 mg/L,
1000 mg appears to be distributed in 100 L ( dose/volume=
concentration). Volume of distribution has nothing to do with the
actual volume of the body or its fluid compartments but rather
involves the distribution of the drug within the body.
Following table summarizes the extent of distribution based on Vd (L)
in humans:
Vd, L Extent of Distribution
5 Only in Plasma
5-20 In extra cellular fluids
20-40 In total body fluids
>40 Bound to peripheral tissues
Clearance is the term that describes the efficiency of irreversible
elimination of a drug from the body. We can refer to clearance by a
particular organ, viz., liver, kidney or by the whole body. Total
body clearance is the sum of all the different clearance processes
occurring for a given drug.
Let's consider an example in rats: What does it mean if the hepatic
clearance of a particular drug is 10.35 mL/min and the hepatic blood
flow is 13.8 mL/min? It does mean that two thirds (10.35/13.8) of the
drug entering the liver in the blood is irreversibly cleared by the
liver in single pass. The value of two thirds for this drug is called
the hepatic extraction ratio and is simply one minus the ratio of
concentration of drug in blood leaving the liver to that in blood
entering the liver. Clearance is the one parameter that determines
the maintenance dose required to achieve a desired plasma levels.
Hope this helps.
Good Luck.
Regds,
Syed
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Hello,
Kindly thanks to all for your reply. I understand that the extent of
distribution of drugs are controlled by two main physicochemical
properties: protein binding and partition coefficient.
I have another question - is there a similar information available
between the extent of distribution and Vd for other species (rat,
dog, mouse, monkey...) like human?
Any literature reference regarding a rough estimation of relationship
between the extent of distribution and Vd for various species would
be very helpful.
Thanks again,
Anila
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The following message was posted to: PharmPK
Anita:
There is much more to drug distribution in a living system than
solely a physicochemical environment. There are membranes, there are
transporters (influx and efflux), there is metabolism. They all have
to be taken into account.
--
Professor Walter Wolf, Ph.D. Distinguished Professor of
Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
Chair, Biomedical Imaging Science Initiative
University of Southern California 1985 Zonal Ave., Los Angeles, CA
90089-9121
E-Mail: wwolfw.at.usc.edu
Telephone: 323-442-1405
Fax: 323-442-9804
http://www.usc.edu/research/initiatives/bisi/
http://www.usc.edu/schools/pharmacy/faculty_directory/detail.php?id=59
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The following message was posted to: PharmPK
Dear Anila,
The best method for examining distribution in tissues between animals
and
human is physiologically based pharmacokinetics (PBPK). There are
numerous
publications on this subject. PBPK modeling allows you to estimate how a
drug will partition into various tissues, from which a total steady
state
volume of distribution (Vss) can be estimated.
GastroPlus(tm) includes the ability to run PBPK simulations in human
(Western or Asian populations), rat, dog, mouse, and monkey. Kps are
calculated using a modification of the method developed by Rodgers and
Rowland that eliminates some problems that method has with certain
compounds.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-at-.simulations-plus.com
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