Evaluation of human liver slices and reporter gene assays as systems for predicting the cytochrome p450 induction potential of drugs in vivo in humans.
OBJECTIVE
The aim of the study was to investigate the feasibility of predicting human in vivo cytochrome P450 (CYP) induction properties of drugs using in vitro methods.


METHODS
The CYP induction potential of compounds was tested in human liver slices and in reporter gene assays for the aryl hydrocarbon receptor (AhR) and the pregnane X receptor (PXR).


RESULTS
In human liver slices, CYP activities decreased dramatically over the experimental period, whereas mRNA levels could reliably be used to investigate CYP1A, 2C9, and 3A4 induction. However, the interindividual variations and demanding experimentation limit the use of liver slices in screening programs. Reporter gene assays are robust and reliable assays, amenable to high throughput screening. Several compounds activated AhR. The relevance of this activation, however, needs to be further investigated since there are no clear reports on drugs inducing CYP1A in vivo. The results from the PXR assay could be used to correctly classify compounds with known CYP3A induction properties when relating in vivo AUCtot to PXR EC50 values.


CONCLUSIONS
Liver slices are a valuable model to study the regulation of a larger number of enzymes by single compounds. The PXR reporter gene assay could be used as a reliable screening method to predict CYP3A induction in vivo.
Persson
Kajsa P
KP
DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, 431 83, Mölndal, Sweden. kajsa.p.persson@astrazeneca.com
Ekehed
Susanne
S
Otter
Charlotta
C
Lutz
E S Mareike
ES
McPheat
Jane
J
Masimirembwa
Collen M
CM
Andersson
Tommy B
TB
D000368:Aged; D002460:Cell Line; D002470:Cell Survival; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics*; D004790:Enzyme Induction / Q000187:drug effects*; D005069:Evaluation Studies as Topic; D005260:Female; D017930:Genes, Reporter / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D028321:Plant Preparations / Q000494:pharmacology; D011237:Predictive Value of Tests; D000077297:Pregnane X Receptor; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D028321:Plant Preparations; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D012313:RNA; D003577:Cytochrome P-450 Enzyme System