RE: Changing Clearance over time : Enzyme auto-induction

From: Johan.Gabrielsson@astrazeneca.com Subject: RE:[NMusers] Changing Clearance over time : Enzyme auto-induction Date: Mon, August 9, 2004 1:59 am Dear Partha, Leonid et al, Interesting discussion. May I propose a first-order induction function (since often enzyme reactions can be approximated to that) as an alternative to the previously proposed models. Namely, CL = CLinduced -(CLinduced - CLpre)*exp(-kout*(t-Tlag)) where kout corresponds to the fractional turnover rate of the induced enzyme, CLpre the pre-induction clearance (your CL0 I suppose), CLinduced the clearance at steady-state post-induction, and Tlag the lag-time for induction to occur (I suppose your NewT parameter). I have personally applied this relationship (taken from the textbook of Gibaldi and Perrier 1982, pgs. 304-305) at several occassions. The nice thing about the model is that it gives you some info about the apparent fractional turnover-rate (and turnover time) of the inducing enzyme, provided the rate limiting step is the change of the amount of enzyme rather than the half-life of the drug (T1/2kout >> T1/2K(drug)) and that the turnover rate (production) rather than the fractional turnover rate (loss) of enzyme is affected. I have some documented practical examples of simultaneous pre-, peri- and post-induction modelling after repeated dosing (p.o. and i.v.), that I'll be happy to share if you are interested. :-) Johan