PharmPK Discussion - Vss/F

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On 5 Apr 2004 at 09:59:47, Wendy Putnam (wsputn.-a-.yahoo.com) sent the message

Dear all,
Given that Vss=CL*MRT for an IV bolus dose, does it follow that for an
extravascular dose, Vss/F = CL/F*MRTsys where MRTsys = (AUMC/AUC)sys =
MRT + MIT?
Thanks,
Wendy

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On 6 Apr 2004 at 07:40:36, Nick Holford (n.holford.at.auckland.ac.nz) sent the message


Wendy,
Sorry but its not that easy to compute Vss/F from AUMC and AUC. A
convention for nomenclature is to refer to MRT (mean residence time) as
being the sum of MDT (mean disposition time) and MIT (mean input time).
MDT refers to the disposition of the molecule due only to distribution
and elimination processes. MIT is controlled by the input process.
Some common parametric equivalences are MIT=0 for a bolus input,
MIT=1/KA for a first order input and MIT=duration of input process for
a zero order input.
If you calculate MRT from AUMC and AUC you can then make a guess at MIT
under the assumption of some input model and derive MDT=MRT-MIT. Given
MDT you can then get Vss/F from CL/F*MDT.
Nick
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/

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On 6 Apr 2004 at 10:44:18, David Bourne (david.aaa.boomer.org) sent the message

[A correction and a few replies - db]
Maria,
Thanks for pointing out this typo... :-)
You are quite correct the MIT for constant rate input is the mean of
the input duration for each molecule and thus it is at the mid-point of
the input duration.
Nick
--
Dear Nick,
You wrote in reply to Wendy:
"MIT=duration of input process for a zero order input."
Please note that MIT is HALF of the duration of the input process for a
zero
order input.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
--
Further to the explanations offered by Dr Holford, the MIT for a zero
order
input (eg IV infusion) is more commonly expressed as MIT=T/2, where T
is the
duration of input/infusion.
Brendan Johnson, PhD
UNC/GlaxoSmithKline Pharmacokinetics Fellow
Division of Drug Delivery and Disposition
School of Pharmacy, C.B. #7360 Kerr Hall
University of North Carolina at Chapel Hill
Chapel Hill, N.C. 27599-7360
Phone: + 1 919 966-7144
Fax: + 1 919 966-0197
Email: brendan.johnson.at.unc.edu
--
Nick - I believe the MIT for a zero-order infusion is equal to T/2
where T
is the duration of the infusion.
Regards, Jeff
Jeff Wald, PhD
Clinical Pharmacokinetics/Modeling and Simulation
Neurology and GI
RTP, NC
--
Wendy and Nick,
For an input of zero order the MRT will be half the input time not total
duration of input time.  For some other calculations related to this
topic
you may want to refer to:
Straughn AB.  Model-independent steady-state volume of distribution.
J Pharm Sci. 1982 May;71(5):597-8
Some of the original equations related to multiple zero order infusion
dose calculations of Vss reported in the literature are incorrect.
Art Straughn, Pharm.D.
Professor and Director
Drug Research Laboratory
University of Tennessee
874 Union Ave
Suite 5P
Memphis, TN  38163
E-mail: ASTRAUGHN.aaa.UTMEM.EDU
Phone: (901) 448-6033
Fax:       (901) 448-6940
--

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