RE: Drug-metabolite kinetics

From: "BRUNO, Rene" <Rene.BRUNO@RP-RORER.FR> Subject: RE: Drug-metabolite kinetics Date: Mon, 5 Jul 1999 09:47:30 +0200 > Be careful I believe that this model may have identifiability problems. As > it is written, CL (parent drug clearance should refer to clearance of all > parent drug elimination routes except this particular metabolic route (it > is accounted for by KF in the equation). In addition I don't think VMT is > identifiable (as CLM) unless you know the fraction of parent drug > converted to this particular metabolite (a problem similar for parent drug > CL and VP in case of an oral drug, you need to know F, the absolute > bioavailability). > An alternative code is this one (using ADVAN 6). The parent has 3 compartment IV route and the metabolite 2 compartments (compt 4 and 5) : ... $SUBROUTINES ADVAN6 TRANS1 TOL=5 $MODEL NCOMPARTMENTS=5 NPARAMETERS=10 COMP=(CENTRAL DEFDOSE NOOFF) COMP=('PERIPH.' NOOFF) COMP=('PERIPH.' NOOFF) COMP=('METAB.' DEFOBS NOOFF) COMP=('METAB.' NOOFF) $PK ... ; parent parameters TVK14=THETA(1) K14=TVK14*EXP(ETA(1)) TVK45=THETA(2) K45=TVK45*EXP(ETA(2)) TVK54=THETA(3) K54=TVK54*EXP(ETA(3)) TVK40=THETA(4) K40=TVK40*EXP(ETA(4)) K=CL/V ; K elimination for parent, all routes S1=V ; Scaling for parent S4=1 ; Scaling for the metabolite, should be V4 but it is unidentifiable since we don't know the fraction of parent CL accounted for by this metabolic route $DES DADT(1)=A(2)*K21+A(3)*K31-A(1)*(K12+K13+K) ; eq for parent DADT(2)=A(1)*K12-A(2)*K21 ; eq for parent DADT(3)=A(1)*K13-A(3)*K31 ; eq for parent DADT(4)=A(1)*K14+A(5)*K54-A(4)*(K45+K40) ; eq for metabolite. As we fixed V4 = 1, then K14 estimate is actually K14/V4 DADT(5)=A(4)*K45-A(5)*K54 ; eq for metabolite