autoinhibition

Dear nmusers, Could anyone support me with nonmem code for a drug undergoes in vivo hepatic metabolism leading to formation of a metabolite. This metabolite has the ability to inactivate parent drug transformation. Both parent and metabolite data can be fitted with a single model of two-compartment. thanks in advance khaled

Hi Khaled, Previously Mats Karlsson suggested a model for autoinduction for a compound using a hypothetical enzyme compartment. I have used that for various types of dosing regimens. You could adapt this into autoinhibition of metabolite formation. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&Te rmToSearch=10594468&ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubm ed_ResultsPanel.Pubmed_RVDocSum http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&Te rmToSearch=10848719&ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubm ed_ResultsPanel.Pubmed_RVDocSum Plotting A(1), A(2) and A(3) will show how these compartments work. The enzyme compartment needs to be initialized with an AMT of 1 in the dataset for each ID. I have suggested some code below for 1-comp parent, 1-comp metabolite without absorption and complete transformation from parent to metabolite. No doubt you can expand this to your desired 2-comp model. $SUBROUTINES ADVAN6 TOL=3 $MODEL COMP=(CENTRAL) COMP=(ENZ) COMP=(METAB) $DES CM=A(3)/V3 DADT(1)=-(K13*A(2))*A(1) ;;parent conc DADT(2)=KENZ-KENZ*A(2)*(1+(CM/(CM+IC50))) ;; hypothetical enzyme DADT(3)=K13*A(1)-K30*A(3) ;; metabolite conc With friendly regards, Thomas Thomas Kerbusch, PhD Section Head PK-PD Dept. CPK N.V. Organon - XW 3133 PO Box 20 5340 BH Oss The Netherlands tel: +31 412 661621 cell: +31 613045046 (intern 4936) fax: +31 412 662542 [EMAIL PROTECTED]