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Dear Colleagues.
We are working On PK drug-drug interaction, with some drugs both Vd and Cl increased or
decreased but with other drugs Vd increases and Cl decreased. I wonder how to explain
these results. Looking for ur guidance.
Dr Zafar
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Dear Dr Zafar
1. Whenever CL and V increase or decrease - most likely the pre-systemic metabolism is
affected. That is, the bioavailability is altered. So if you check the terminal half-life
in the two groups (with vs without interacting drug) they should be similar. In fact most
important drug drug interactions I believe are those that affect bioavailability.
2. With respect to changes in CL- the systemic CL is altered by the interacting drug.
3. It's challenging to comment on changes in V - first it depends on what V you are
referring to. Unfortunately most reported V are the so-called Vz (terminal volume). If
that is what you are referring to, then these changes are not relevant. But if you are
referring to more physiologically relevant Volume such as Vc (central compartment) or Vp
(tissue) then you will need to probe deeper into the potential mechanisms (?protein
binding changes). I have to say it is rarer to find effects on V- not unheard of though.
Joga Gobburu, PhD FCP MBA
Professor
School of Pharmacy|School of Medicine
University of Maryland, Baltimore
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Dear Dr. Zafar,
Adding to the discussion put forth by Dr. Gobburu, regarding
simultaneous increase or decrease (to a similar extent) in Vd and Cl:
one publication that that you might want to refer to is "Clin
Pharmacol Ther. 2001 Oct;70(4):317-26". This article describes the
effect of St John's Wort on pre-systemic metabolism of midazolam
(victim drug), that ultimately affected its oral bioavailability.
With regards to the second scenario i.e. increased Vd and reduced Cl,
it will be interesting to see if your victim drug is a substrate of
efflux transporters (P-gp). Efflux transporter inhibition
(specifically at renal tubules) might lead to an increase in Vd and
decrease in Cl of the substrate molecule. A perfect example for this
kind of PK interaction was observed with digoxin upon
co-administration of ritonavir. (Clin Pharmacol Ther. 2004
Jul;76(1):73-84.), wherein the
I also encourage you to refer to Dr. Lez Benet's review article that
comprehensively demonstrates the effects of efflux transporters on
volume of distribution. (AAPS J. 2009 Jun;11(2):250-61)
Hope this helps.
-Mukul
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Dear All:
With all this emphasis on clearance, It might be good to keep in
mind that what we often want to know is the actual amount of drug
(uncontaminated by any perceived volume term) transferred from one
compartment to another per unit time. Getting volume out of the way and
using a rate constant instead (since both K and clearance can be used
interchangeably) can often be most useful in this regard. I know a lot of
people are emotionally committed to clearance as supposedly the most
relevant biological parameter, but K and clearance are really quite
interchangeable, and it is often useful to write the differential equations
in terms of amount rather than concentration, with the output of the system
being that the observed concentration is the amount in a stated compartment
divided by its apparent volume.
Very best regards,
Roger W. Jelliffe, M.D., F.C.P.
Professor of Medicine,
Co-Director, Laboratory of Applied Pharmacokinetics
www.lapk.org
USC Keck School of Medicine
2250 Alcazar St, Room 134-B
Los Angeles CA 90033
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