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Hi, Everyone,
I am doing screening for drug development in PK field. Lately I have
several drugs (or compounds) showed very small AUC, for example, one of
them was 3.05ughr/ml (Cmax 0.2-0.5ug/ml) at 50mg/kg per oral in mice.
But AUC(i.v.) was very very small also, at 10mg/kg by i.v. bolus
injection, AUC was 0.81ughr/ml(Cmax only 0.6ug/ml, usually about 20ug/ml
at same dosing level for hundreds of other compounds what I have
screened), theoretically equavalent to 4.05 at 50mg/kg dosing (We
assume that it follows linear kinetics during this dosing range), so
this drug's bioavailabity turned to be 75%, it is surprisingly high. My
explanation is this drug has extremely fast and high tissue
distribution.
Is anybody has any suggestions, ideas or comment about this data? Is
this possible? What else explanation could be?
Thanks in advance, sorry about question ran too long.......
Lihong Gao, Ph.D.
Pharmacokinetic Group
Shionogi, Boresearch Corp.
Lexington, MA
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[A few replies - db]
From: "Aziz Karim"
To:,
"Multiple recipients of PharmPK - Sent by"
Subject: Re: PharmPK bioavailability question
Date: Thu, 5 Nov 1998 11:36:50 -0600
X-Priority: 3
What is the blood/plasma concentration ratio of the drug? If the erythrocyte
uptake is high then one should determined the blood clearance besides plasma
clearance of the drug.
I can think of two obvious possibilities to explain your data: 1) high
erythrocyte uptake and 2) sequestration of the drug in some tissues/organs
resulting in high volume of distribution.
I am sure there are other explanation as well.
Regards,
Aziz Karim
---
Date: Thu, 05 Nov 1998 13:25:28 -0500
From: Nabil B. Darwazeh
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK bioavailability question
Mime-Version: 1.0
is it possible that this drug is precipitating upon i.v. administrations
(do you have any observation such that if you add some of the injection
solution to a sample of plasma, the drug will precipitate)
Nabil
---
From: "Bruce CHARLES"
Organization: School of Pharmacy
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Date: Fri, 6 Nov 1998 09:31:56 +1000
MIME-Version: 1.0
Subject: Re: PharmPK bioavailability question
X-Confirm-Reading-To: "Bruce CHARLES"
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Priority: normal
Send reply to: PharmPK.aaa.pharm.cpb.uokhsc.edu
Date sent: Thu, 5 Nov 1998 09:16:09 -0600
From: Lihong Gao(by way of David_Bourne)
To: Multiple recipients of PharmPK - Sent by
Subject: PharmPK bioavailability question
To check the distribution hypothesis the obvious ones that spring to mind are:
1. Continue further blood sampling for as long as your assay sensitivty is
OK, to
identify deep compartments.
2. Since it is in mice do tissue analysis (e.g. mcg drug/gram dry tissue mass)
particularly fat, bone and muscle (as well as the major organs).
Cheers,
BC
Bruce CHARLES, PhD
Senior Lecturer
School of Pharmacy
The University of Queensland
Brisbane, QLD Australia 4072
TEL: +61 7 336 53194
FAX: +61 7 336 51688
Email: Bruce.aaa.pharmacy.uq.edu.au
---
X-Originating-IP: [194.95.249.19]
From: "Krishna Devarakonda"
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK bioavailability question
MIME-Version: 1.0
Date: Fri, 06 Nov 1998 04:56:28 PST
DEAR Dr Gao,
From your data what is evident is that the volume of distribution of
your compound is very high. From i.v. data [V=D/C(0)] it is as high as
16.7 l/kg, where as with the other drugs it is only about 0.5 l/kg. It
implies that this compound has nearly 34 times higher vol.distr. I am
sure that you are measuring the free drug concentration for computing
the abs.bioavailability. I dont think that high vol.distr. can affect
the F and hence it is not surprising that the F is 75%. If your drug
undergoes extensive first pass metabolism and / or there is an
incomplete absorption, then you can expect low bio-availability (Your
drug does not seem to undergo).
Whether it undegoes faster distribution or not can be said if you have
the plasma conc. - time profile and pkin data (like distribution rates).
It is quite possible that the drug is extensively protein bound or is
being taken up by a deep tissue compartment.
Good Luck!
D.R.Krishna,Ph.D
AvH Scientist
Dr.Margarete-Fischer-Bosch-Institue
of Clinical Pharmacology
Auerbachstr.112
70376 Stuttgart, Germany
Tel. Off: +49-711-8101-3753
Fax: +49-711-85 92 95
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