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Measuring pharmacokinetic properties of established and potential PET-tracers

Kofoed Bech, Lasse LU (2012) KEMR36 20111
Department of Chemistry
Abstract
Measuring pharmacokinetic properties is notoriously difficult. The invitro/ex vivo laboratory experiments seek to mimic the physiological
responses of the body to the drug, but it rarely gives a good estimate of what happens in vivo.
Lipophilicity is traditionally measured by the shake-flask method,in which the distribution of the analyte between two immiscible phases
(one organic, one aqueous) is investigated. It is a tedious process, and faster and less laborious methods are desirable. Calibration of
a column/eluent-system on HPLC has been proposed, but the chromatographic process does not mimic the distribution process perfectly,
and the results need to be related to each other.
In the research group, plasma protein binding is... (More)
Measuring pharmacokinetic properties is notoriously difficult. The invitro/ex vivo laboratory experiments seek to mimic the physiological
responses of the body to the drug, but it rarely gives a good estimate of what happens in vivo.
Lipophilicity is traditionally measured by the shake-flask method,in which the distribution of the analyte between two immiscible phases
(one organic, one aqueous) is investigated. It is a tedious process, and faster and less laborious methods are desirable. Calibration of
a column/eluent-system on HPLC has been proposed, but the chromatographic process does not mimic the distribution process perfectly,
and the results need to be related to each other.
In the research group, plasma protein binding is traditionally measured by equilibrium dialysis, a method that relies on passive diffusion.
This may take a long time (+24 hours), and ultracentrifugation is proposed as a new and much faster method (app. 1 hour).
In this project, new methods for measurement of lipophilicity and plasma protein binding are developed and evaluated. The group of
compounds measured by the methods are all established or potential PET-tracers.
LogD-values obtained by shake-flask and HPLC was not in accordance, especially not for logD-values in the low range. For plasma
protein binding, accordance between the methods was found in the range 0-10 % free fraction, but for higher free fractions accordance
was only found for some compounds. (Less)
Please use this url to cite or link to this publication:
author
Kofoed Bech, Lasse LU
supervisor
organization
course
KEMR36 20111
year
type
H2 - Master's Degree (Two Years)
subject
keywords
HPLC, equilibrium dialysis, Analytisk kemi, Lipophilicity, shake-flask, plasma protein binding, ultracentrifugation.
language
English
id
2862862
date added to LUP
2012-08-14 14:13:03
date last changed
2012-08-14 14:13:03
@misc{2862862,
  abstract     = {Measuring pharmacokinetic properties is notoriously difficult. The invitro/ex vivo laboratory experiments seek to mimic the physiological
responses of the body to the drug, but it rarely gives a good estimate of what happens in vivo.
Lipophilicity is traditionally measured by the shake-flask method,in which the distribution of the analyte between two immiscible phases
(one organic, one aqueous) is investigated. It is a tedious process, and faster and less laborious methods are desirable. Calibration of
a column/eluent-system on HPLC has been proposed, but the chromatographic process does not mimic the distribution process perfectly,
and the results need to be related to each other.
In the research group, plasma protein binding is traditionally measured by equilibrium dialysis, a method that relies on passive diffusion.
This may take a long time (+24 hours), and ultracentrifugation is proposed as a new and much faster method (app. 1 hour).
In this project, new methods for measurement of lipophilicity and plasma protein binding are developed and evaluated. The group of
compounds measured by the methods are all established or potential PET-tracers.
LogD-values obtained by shake-flask and HPLC was not in accordance, especially not for logD-values in the low range. For plasma
protein binding, accordance between the methods was found in the range 0-10 % free fraction, but for higher free fractions accordance
was only found for some compounds.},
  author       = {Kofoed Bech, Lasse},
  keyword      = {HPLC,equilibrium dialysis,Analytisk kemi,Lipophilicity,shake-flask,plasma protein binding,ultracentrifugation.},
  language     = {eng},
  note         = {Student Paper},
  title        = {Measuring pharmacokinetic properties of established and potential PET-tracers},
  year         = {2012},
}