# PharmPK Discussion - CYP450 interactions and hepatic extraction ratio

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• On 17 Apr 2007 at 10:25:46, Sergej Ramusovic (S.Ramusovic.at.uni-duesseldorf.de) sent the message
`The following message was posted to: PharmPKHi to all,firstly i would like to thank everyone discussing here, these threadsare enlightening to read, especially for beginners inpharmakokinetics like me.I am referring to the discussion "CYP450 interactions and hepaticextraction ratio".Trying to show the effects of a change in CLint (intrinsic clearance)on Css yields the same ratio of change for low and high extractiondrugs, if you use the formulas of the well stirred model for CL and F(where F=1-E) predictions and apply them to the example of Mr. Cawello.The reason for this was given by Mr. Proost:"From the basis equation during steady state, input = output, itfollows that the relationship between dosing rate and Css isdependent on the ratio CL / F:Dose / tau =  CL / F * CssThis ratio CL /F is proportional to the intrinsic clearance (CLint),and thus to the metabolic capacity, IRRESPECTIVE OF THEHEPATIC EXTRACTION RATIO.This can be checked easily from the numerical examples given byWilli Cawello, or by combining the equation for the hepatic clearance,liver blood flow and intrinsic clearance given by Mike Leibold (notethatthe fraction unbound should be added to the equation, but thatdoes not matter for the present discussion), and the equationF = 1 - EH."The factor CL/F can be rewritten using the terms of the well stirredmodel:(Q*fub*CLint)/Q+fub*CLint / (1-(fub*CLint)/Q+fub*CLint)which is indeed proportional with respect to changes in CLint.The relative impact of changing Css will be the same for anynumerical value of CLint and therefore for low and high extractiondrugs alike.But what does that mean now? Am I wrong assuming that the greaterimpact of changing CLint for low extraction drugs on Css can bemodeled using the well stirred model terms?If that is the case, how can the changes in Css be described in abetter way?Sorry for bothering you with that topic again, I hope it is not tootrivial.Thank you all in advance,yours,Sergej RamusovicPharmacistHeinrich-Heine-University DuesseldorfClinical Pharmacy and PharmacotherapyGeb.26.22.02.21Universitaetsstr. 140225 DuesseldorfGermany`
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