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Dear collegues,
The following question concerns the in vitro-in vivo extrapolation of=20
drug-drug interaction data and the use of the in vitro half-life=20
(t1/2) approach.
Currently, the in vitro-in vivo extrapolation of drug-drug=20
interactions based on in vitro results is of great interest. Up til=20
now extrapolations have been based on in vitro determined inhibitor=20
constants (Ki=92s). The calculation of these Ki=92s is based on=20
inhibition of metabolite formation.
Another way of studying inhibition is to evaluate the effect of an=20
inhibitor on the disappearance of the substrate.
Recently, several publications (e.g. Obach Drug Met Dispos 1999;=20
27:1350-1359) have used the in vitro t1/2 approach (hepatic=20
microsomal lability data) for the estimation of the in vitro Clintr=20
of a drug, based on the disappearance of the substrate in an in vitro=20
system with human liver microsomes. Clintr can be calculated=20
according to Clint=3DV * 0.693/t1/2 with V, the incubation volume and=20
t1/2, the in vitro half-life as calculated from the log-linear part=20
of the % remaining substrate as a function of time.
This calculated Clint can then be used for scale-up to reflect the=20
Clintr in vivo, followed by insertion into a model of hepatic=20
extraction (well-strirred model) in order to predict the blood=20
clearance of a drug.
We would like to use this t1/2 approach for the prediction of drug-=20
drug interactions. We would determine the t1/2 of a substrate in the=20
absence and in the presence of inhibitor. In each case, a Clint can=20
be calculated.
Since, theoretically the Clint(control)/Clint(+inhibitor) ratio=20
equals the ratio AUC(control)/AUC(+inhibitor) for orally administered=20
drugs, the Clint ratio could be used for prediction of the in vivo=20
observed AUC ratio.
=46irstly, we would like to know whether this approach for in vitro-in=20
vivo extrapolation of drug-drug interactions is feasible and/or=20
whether someone could give us some valuable suggestions regarding=20
this approach.
The second problem with this approach is the choice of the inhibitor=20
concentration in the incubation mixture: I would suggest using=20
inhibitor concentrations reported in the literature under=20
steady-state conditions; whether the free (unbound) or the total=20
plasma concentrations should be used remains problematic.
We would be very grateful for any comments or suggestions.
Thanks in advance.
Sincerely,
Alex Hemeryck
**************************************** Alex Hemeryck Pharmacist=20
Heymans Institute of Pharmacology University of Ghent Medical School=20
De Pintelaan 185 B-9000 Gent Tel: +32-9-2403370 Fax: +32-9-2404988=20
e-mail: Alex.Hemeryck.-a-.rug.ac.be=20
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