RE: [NMusers] autoinhibition

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
Thomas.Kerbusch_at_organon.com
-----Original Message-----
From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com]
On Behalf Of Khaled Mohammed Abduljalil
Sent: Friday, 22 June, 2007 12:50
To: nmusers_at_globomaxnm.com
Subject: [NMusers] 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

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Received on Fri Jun 22 2007 - 09:13:51 EDT