enzyme auto inhibition PK model

Hi Yuyan, We modeled the autoinduction of artemisinin (Gordi T, Xie R, Huong NV, Huong DX, Karlsson MO, Ashton M.: A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction.Br J Clin Pharmacol. 2005 Feb;59(2):189-98.) The model includes a hepatic compartment, whose drug concentrations increases the production rate of an enzyme compartment. The increased enzyme levels result in increased intrinsic clearance, which affect the extraction ratio (EH) of the compound assuming a well-stirred model. The changes in EH influence both the bioavailability as well as the clearance of the compound. The model should work in your case (inhibition) as well: all you'll need to do is to let the hepatic drug amounts to inhibit the production (or increase the elimination) of the enzyme compartment. I believe the nice thing about the model is that it assumes hepatic, and not plasma, drug levels to change the enzyme amounts. This has two advantages: it is more physiologically relevant (most of the time), and the effect is not influenced by changes in plasma concentrations, which are the consequence of induction or inhibition. Let me know if you want the NONMEM control stream for the model. Toufigh