Dear All:Back to the Top
For a 3-hydroxy pyrazole chemical series, about 25 compounds tested in
rat PK have shown high CL (more than hepatic blood flow). These CL
values werecalculated based on plasma data.Out of curiosity, we
spiked one compound in blood and rapidly separated the plasma and blood
components (Time = 0) and found that 75% of the compound was in the
blood and 25% in plasma. Thus, all along we were overestimating the CL
based on plasma data. These compounds are targeted for CNS
indication. Due to the high CL (based on plasma data) we
concludedthat the oral bioavailability of the compounds was low. How
do we proceed with future evaluation of these compounds for
bioavailability? Should we use plasma data or blood data? What
blood:plasma ratio necessitates the use of whole blood rather than
plasma for routine PK studies?
Please advise.
Garcia
Propofol, an anesthetic, partitioned rapidly to the RBC requiringBack to the Top
analysis on blood data only. Other drugs such as paclitaxel
partitioned more slowly into RBC because of the formulation vehicle.
Therefore, PK is more reliable with blood bioanalytical method.
Dear Garcia,Back to the Top
I believe ionization of NCE's at plasma pH of 7.4 is
one of the major limitation factor to determine the uptake into
erythrocytes (RBC's) and hence the pKa value of NCEs. For example
Sulfanilamide with pKa of 10.42 is practically unionized at plasma pH
of 7.4,and hence the free and rapid diffusion into RBCs is expected
whereas Sulfadiazine with a pKa of 6.48 is expected to be ionized to
the extent of 90% at plasma pH of 7.4 and is readily taken up by RBCs.
Concentration of NCE in RBC can be readily
determined when you have a Hematocrit value ( which can be easily
determied by autoanalyzer)by substituting into:
= whole blood concentration -[ Plasma conc (1-Hv)]
------------------------------------------------- * 100
Hv
where Hv is the Hematocrit value.
On the other hand, Dr EA de Bruijn of Belgium
developed a device, based on measurement of sediment [ MESED]
technology, which permits the simultaneous analysis of NCEs in plasma
and RBCs as well. The MESED instrument is madeof polycarbonate " Lexan"
and can be reused. You can have the further information fronm Dr O
Driessen, Fabre, Mesed instruments ( Tel-0032 87 786522; Fax-0032 87
786762). I would recommend you to look at the following literatures:
1. RBCs: a neglected compartent in topotecan pharmacokinetic analysis
in Anticancer drugs 2003 Mar; 14(3):227-32
2. RBC: a neglected compartment in pharmacokinetics and
pharmacodynamics in Pharmacol Rev 1997 Sep; 49(3) :279-95
Hope this helps.
Regards,
S Syed Mustafa,
Research Associate,
Drug metabolism & Pharmacokinetics,
Dr Reddys Research Foundation,
Bollaram Road, Miyapur,
Hyderabad-500049 INDIA
ERRATABack to the Top
-
DearGroup,
Kindly read it in my response as "whereas Sulfadiazine with a pKa
of 6.48 is expected to be ionized to the extent of 90% at plasma pH
of 7.4 and is not easily diffused intothe RBCs"
Which was by mistakeappeared as" whereas Sulfadiazine with a pKa
of 6.48 is expected to be ionized to the extent of 90% at plasma pH of
7.4 and is readily taken up intothe RBCs"
I Regret for the inconvenience caused..
Regards,
S Syed Mustafa,
Research Associate,
Drug metabolism & Pharmacokinetics,
Dr Reddys Research Foundation,
Bollaram Road, Miyapur,
Hyderabad-500049 INDIA
Hi Mustafa,Back to the Top
Your comment on pKa and ionisation is true for an acidic drug. But,
Sulfadiazine being a basic drug and with a pKa of 6.48 will ionise to
about
10% only at pH 7.4. Since most of the drug is in the unionised form, it
should diffuse through RBC or for that matter any biological membrane.
Hope I am not confusing you.
Regards,
Kasiram.
Back to the Top
Dear Syed Mustafa,
We routinely determine the conc. of drug in plasma by any of the
methods (precipitation, liq-liq extraction etc), how can we determine
the conc. of the drug in the whole blood? do you have any literature
protocol which you can share to determine the whole blood conc? Also
can you give me the reference from where you got the formula to
calculate conc. of compounds in RBC's
Regards,
Suresh.B.L
Hi Mustafa,Back to the Top
I think I have confused you regarding Sulfadiazine by saying it as a
weak
base while it is actually a weak acid. You are right in saying that it
ionises to about 90% at physiologic pH being a weak acid with pKa of
6.4 and
that it fails to diffuse into RBCs at pH7.4.
Apologies for confusing the group.
Kasiram.
Dear Garcia,Back to the Top
Here arethe list ofreferences that you have been looking for.
1.Robinson MA, Mehvar are Enantioselective distribution of Verapamil and
norverapamil into human and rat erythrocytes: the role of plasma
protein binding: Biopharm Drug Dispos 1996; 17:577-587
2.Stereoselective Pharmacokinetics of Ifosfamide in male and female
Wistar rats AAPS Pharmsci 2000;2(2) article 17 (www.pharmsci.org)
Hope this helps.Good Luck.
Syed Mustafa S,
Research Associate,
Drug Metabolism and Pharmacokinetics,
Dr Reddy's Research foundation,
Bollaram Road, Miyapur,
Hyderabad-500049 INDIA
www.drreddys.com
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