gamma phase?

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