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: <http://www.pdn.cam.ac.uk/staff/jarvis>www.pdn.cam.ac.uk/staff/jarvis
