Back to the Top
From discussions with a PK consultant, drugs like daptomycin that
are "highly protein bound but have low Volume of Distribution and low
Clearance, should theoretically not displace other highly serum
protein bound drugs to any measurable or clinically relevant degree"
Agree or disagree?
Dave
Back to the Top
Dave,
I think considering the dose helps in this case. Displacement of
drugs bound to plasma proteins will only reach significance when the
total plasma concentration of the displacing drug approaches that of
the plasma protein responsible for the binding. As a simple thought
experiment, dissolve the whole dose in the plasma volume, and convert
the concentration to molarity using the molecular weight. You find
that for many antibiotics - sulfa drugs, penicillins, etc - with
doses around 10mg/kg or higher, the maximum theoretical total plasma
concentration exceeds 1mM, which is much higher than the normal
concentration of human serum albumin around 0.68mM (and could be
lower). In this situation, displacement is a possibility.
For daptomycin, at 4mg/kg and with MW 1621, the maximum plasma
concentration assuming no distribution is 0.068mM, which is 1 tenth
of the albumin concentration. The only drug you could possibly
displace/interact with would be a high dose small molecule
antibiotic, and then only by 10%.
I know this is oversimplified - Cmax concentration is much lower,
albumin has multiple binding sites, etc. Any other views?
Ted Parton
Back to the Top
Displacement occurs or not will depend upon the relative affinities
of the compound for the serum proteins.
Indranil Bhattacharya
DMPK
Back to the Top
The following message was posted to: PharmPK
It is true that low Vd and a strong binding to plasma proteins implies a
strong retentional effect in plasma, and that displacements
especially if
the concentrations of the molecule is close to saturation will be
difficult.
It seems that the daptomycin is bound to HAS according to a saturable
way as
well as to AAG (Lee et al 1991). On the HSA there are several binding
sites
mainly Site I (the warfarin Site) and site II (the diazepam site) and
only
the characterization of the binding site of daptomycin will make
possible to
predict the potential effects in the drug interactions especially if
they
share the same binding site.
The binding percentage is not sufficient to account for the
possibility of
drug interaction, only affinities will give the best approaches.
I hope this may be useful
Best regards
Francoise BREE
BIOPREDIC
Parc d'affaire de la Breteche
Batiment B1
35760 Saint Gregoire
France
francoise.bree.-a-.biopredic.com
Back to the Top
Dave,
there can be displacemnt when the drugs bind to the same binding site
and more than say 20% of these sites are occupied, however it is
usually not clinically relevant. See the below references for details:
Rolan PE (1994) Plasma protein binding displacement interactions--why
are they still regarded as clinically important? Br J Clin Pharmacol;
37(2):125-8.
Sansom LN, Evans AM (1995)What is the true clinical significance of
plasma protein binding displacement interactions? Drug Saf; 12(4):
227-33.
Benet LZ, Hoener BA (2002) Changes in plasma protein binding have
little clinical relevance. Clin Pharmacol Ther; 71(3):115-21.
Regards,
Markus
Markus Weiss, PhD
ED/DMPK/ADME/ADE
Novartis Pharma AG, Werk Klybeck
WKL-135.4.83
CH-4002 Basel
Switzerland
Phone: +41 61 69 61075
Fax: +41 61 69 65146
Email : markus.weiss.aaa.novartis.com
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)