Dear All
I have a query about basic principles of PK. I am trying to understand the
mechanistic basis for a gamma phase in PK. (The drug that has sparked this
query is gentamicin.) All I can find is the suggestion that it is caused by
slow release of drug from tissues (see figure:
http://www.rxkinetics.com/pktutorial/2_3.html).
As I understand it, following iv administration one can see (assuming all
linear kinetics):
1. alpha phase = distribution. Plasma concentrations fall because of
movement of drug from plasma into the tissues and by elimination of drug
from plasma.
2. beta phase = elimination. Plasma concentrations fall because of
elimination of drug from plasma. Concentration gradient between plasma and
tissues is such that the net movement of drug is from tissues to plasma.
3. gamma phase = "tissue release"?? Once 'all' the drug has been
eliminated 'normally', drug that has accumulated in the tissues is released
very slowly resulting in a slow fall in the plasma concentration.
This "explanation" of the gamma phase (which is my own attempt) seems very
unsatisfactory to me. Surely, once a drug is in the plasma it will be
eliminated in the same way regardless of its concentration (all other things
being equal and for linear PK). While in practice there may be issues of
detection at low concentrations, in principle, clearance should remain the
same and should not be determined by the rate at which the drug enters the
plasma from a "deep" tissue compartment.
The only thing I can come up with is that over an extended period of dosing,
a drug may accumulate slowly and to such an extent that the volume of
distribution increases, so that when dosing stops, although the clearance
mechanism remains the same, the apparent rate constant of elimination has
fallen because the volume is bigger. This would mean that over an extended
dosing period, the volume of distribution would slowly increase. I'm
guessing that after stopping dosing, the volume of distribution would
decrease, but very slowly compared to drug elimination, so that you might
still see a linear (and slower) elimination phase and not a curvilinear
phase as might be expected if the volume of distribution is changing with
time.
To be honest, I'm confused, and have probably just made an idiot of myself!
Any help would be gratefully received.
Gavin
__________________________________________________
Dr Gavin E Jarvis MA PhD VetMB MRCVS
University Lecturer in Veterinary Anatomy
Department of Physiology, Development & Neuroscience
Physiological Laboratory
Downing Street
Cambridge
CB2 3EG
Tel: +44 (0) 1223 333745
Email: <mailto:[email protected]> [email protected]
Web: http://www.pdn.cam.ac.uk/staff/jarvis www.pdn.cam.ac.uk/staff/jarvis
gamma phase?
Dear Gavin,
This washout period reflects the existence of a deep compartment that in the case of gentamicin is represented by the proximal tubules and other tissues. The distribution in the deep compartment is slower than elimination and when the plasma concentration is negligible the redistribution from the deep compartment controls the terminal slope of the plasma concentration-time curve (flip-flop kinetics), however the distribution volume of the deep compartment remain unaltered.
Best regards,
José
Prof. José M. Lanao
Dpt. Pharmacy and Pharmaceutical Technology
Faculty of Pharmacy
University of Salamanca
Spain
Phone: +34 923 294536
Fax: +34 923 294515
E-mail: [email protected]
At 18:26 28/04/2014, Gavin Jarvis wrote:
> Dear All
>
> I have a query about basic principles of PK. I am trying to understand the mechanistic basis for a gamma phase in PK. (The drug that has sparked this query is gentamicin.) All I can find is the suggestion that it is caused by slow release of drug from tissues (see figure: http://www.rxkinetics.com/pktutorial/2_3.html ).
>
> As I understand it, following iv administration one can see (assuming all linear kinetics): 1. alpha phase = distribution. Plasma concentrations fall because of movement of drug from plasma into the tissues and by elimination of drug from plasma. 2. beta phase = elimination. Plasma concentrations fall because of elimination of drug from plasma. Concentration gradient between plasma and tissues is such that the net movement of drug is from tissues to plasma. 3. gamma phase = tissue release?? Once all the drug has been eliminated normally, drug that has accumulated in the tissues is released very slowly resulting in a slow fall in the plasma concentration.
>
> This explanation of the gamma phase (which is my own attempt) seems very unsatisfactory to me. Surely, once a drug is in the plasma it will be eliminated in the same way regardless of its concentration (all other things being equal and for linear PK). While in practice there may be issues of detection at low concentrations, in principle, clearance should remain the same and should not be determined by the rate at which the drug enters the plasma from a deep tissue compartment.
>
> The only thing I can come up with is that over an extended period of dosing, a drug may accumulate slowly and to such an extent that the volume of distribution increases, so that when dosing stops, although the clearance mechanism remains the same, the apparent rate constant of elimination has fallen because the volume is bigger. This would mean that over an extended dosing period, the volume of distribution would slowly increase. Im guessing that after stopping dosing, the volume of distribution would decrease, but very slowly compared to drug elimination, so that you might still see a linear (and slower) elimination phase and not a curvilinear phase as might be expected if the volume of distribution is changing with time.
>
> To be honest, Im confused, and have probably just made an idiot of myself! Any help would be gratefully received.
>
> Gavin
>
> __________________________________________________
> Dr Gavin E Jarvis MA PhD VetMB MRCVS
> University Lecturer in Veterinary Anatomy
> Department of Physiology, Development & Neuroscience
> Physiological Laboratory
> Downing Street
> Cambridge
> CB2 3EG
>
> Tel: +44 (0) 1223 333745
> Email: <mailto:[email protected]>[email protected]
> Web: www.pdn.cam.ac.uk/staff/jarvis">http://www.pdn.cam.ac.uk/staff/jarviswww.pdn.cam.ac.uk/staff/jarvis
Dear José
Thanks for the reply. That does help and has given me something new to go
away and think about.
All best
Gavin
Quoted reply history
-----Original Message-----
From: J.M.Lanao [mailto:[email protected]]
Sent: 29 April 2014 08:28
To: Gavin Jarvis; [email protected]
Subject: Re: [NMusers] gamma phase?
Dear Gavin,
This washout period reflects the existence of a deep compartment that in
the case of gentamicin is represented by the proximal tubules and other
tissues. The distribution in the deep compartment is slower than elimination
and when the plasma concentration is negligible the redistribution from the
deep compartment controls the terminal slope of the plasma
concentration-time curve (flip-flop kinetics), however the distribution
volume of the deep compartment remain unaltered.
Best regards,
José
Prof. José M. Lanao
Dpt. Pharmacy and Pharmaceutical Technology Faculty of Pharmacy University
of Salamanca Spain
Phone: +34 923 294536
Fax: +34 923 294515
E-mail: [email protected]
At 18:26 28/04/2014, Gavin Jarvis wrote:
>Dear All
>
>I have a query about basic principles of PK. I am trying to understand
>the mechanistic basis for a gamma phase in PK. (The drug that has
>sparked this query is gentamicin.) All I can find is the suggestion
>that it is caused by slow release of drug from tissues (see figure:
> http://www.rxkinetics.com/pktutorial/2_3.html).
>
>As I understand it, following iv administration one can see (assuming
>all linear kinetics):
>1. alpha phase = distribution. Plasma
>concentrations fall because of movement of drug from plasma into the
>tissues and by elimination of drug from plasma.
>2. beta phase = elimination. Plasma
>concentrations fall because of elimination of drug from plasma.
>Concentration gradient between plasma and tissues is such that the net
>movement of drug is from tissues to plasma.
>3. gamma phase = tissue release?? Once
>all the drug has been eliminated normally, drug that has
>accumulated in the tissues is released very slowly resulting in a slow
>fall in the plasma concentration.
>
>This explanation of the gamma phase (which is my own attempt) seems
>very unsatisfactory to me.
>Surely, once a drug is in the plasma it will be eliminated in the same
>way regardless of its concentration (all other things being equal and
>for linear PK). While in practice there may be issues of detection at
>low concentrations, in principle, clearance should remain the same and
>should not be determined by the rate at which the drug enters the
>plasma from a deep tissue compartment.
>
>The only thing I can come up with is that over an extended period of
>dosing, a drug may accumulate slowly and to such an extent that the
>volume of distribution increases, so that when dosing stops, although
>the clearance mechanism remains the same, the apparent rate constant of
>elimination has fallen because the volume is bigger. This would mean
>that over an extended dosing period, the volume of distribution would
>slowly increase. Im guessing that after stopping dosing, the volume of
>distribution would decrease, but very slowly compared to drug
>elimination, so that you might still see a linear (and slower)
>elimination phase and not a curvilinear phase as might be expected if
>the volume of distribution is changing with time.
>
>To be honest, Im confused, and have probably just made an idiot of
>myself! Any help would be gratefully received.
>
>Gavin
>
>
>__________________________________________________
>Dr Gavin E Jarvis MA PhD VetMB MRCVS
>University Lecturer in Veterinary Anatomy Department of Physiology,
>Development & Neuroscience Physiological Laboratory Downing Street
>Cambridge
>CB2 3EG
>
>Tel: +44 (0) 1223 333745
>Email: <mailto:[email protected]>[email protected]
>Web:
www.pdn.cam.ac.uk/staff/jarvis">http://www.pdn.cam.ac.uk/staff/jarviswww.pdn.cam.ac.uk/staff/jarvis
>