Persson K.P., Ekehed S., Otter C., Lutz E.S.M., McPheat J., Masimirembwa C.M., Andersson T.B.
DMPK and Bioanalytical Chemistry, AstraZeneca R and D Mölndal, 431 83 Mölndal, Sweden; Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden; Molecular Pharmacology, AstraZeneca R and D Mölndal, 431 83 Mölndal, Sweden; Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden; African Institute of Biomedical Science and Technology, P.O. Box 2294, Harare, Zimbabwe
Persson, K.P., DMPK and Bioanalytical Chemistry, AstraZeneca R and D Mölndal, 431 83 Mölndal, Sweden, Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden; Ekehed, S., DMPK and Bioanalytical Chemistry, AstraZeneca R and D Mölndal, 431 83 Mölndal, Sweden; Otter, C., Molecular Pharmacology, AstraZeneca R and D Mölndal, 431 83 Mölndal, Sweden; Lutz, E.S.M., DMPK and Bioanalytical Chemistry, AstraZeneca R and D Mölndal, 431 83 Mölndal, Sweden; McPheat, J., Molecular Pharmacology, AstraZeneca R and D Mölndal, 431 83 Mölndal, Sweden; Masimirembwa, C.M., DMPK and Bioanalytical Chemistry, AstraZeneca R and D Mölndal, 431 83 Mölndal, Sweden, African Institute of Biomedical Science and Technology, P.O. Box 2294, Harare, Zimbabwe; Andersson, T.B., DMPK and Bioanalytical Chemistry, AstraZeneca R and D Mölndal, 431 83 Mölndal, Sweden, Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden
Purpose. 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. © 2006 Springer Science + Business Media, Inc.
2,3,7,8 tetrachlorodibenzo para dioxin; aromatic hydrocarbon receptor; betamethasone; carbamazepine; cimetidine; clotrimazole; cytochrome P450 1A; cytochrome P450 2C9; cytochrome P450 3A; cytochrome P450 3A4; dexamethasone; diazepam; diclofenac; hyperforin; indometacin; lansoprazole; messenger RNA; mevinolin; naproxen; omeprazole; pantoprazole; paracetamol; phenobarbital; phenytoin; pregnane X receptor; primaquine; rifampicin; troglitazone; unindexed drug; warfarin; adult; aged; area under the curve; article; assay; clinical article; controlled study; enzyme regulation; experimentation; female; high throughput screening; human; human cell; human tissue; in vitro study; in vivo study; liver slice; male; prediction; priority journal; protein induction; reporter gene; screening; Aged; Cell Line; Cell Survival; Cytochrome P-450 Enzyme System; Enzyme Induction; Evaluation Studies; Female; Genes, Reporter; Humans; Liver; Male; Middle Aged; Organ Culture Techniques; Plant Preparations; Predictive Value of Tests; Receptors, Aryl Hydrocarbon; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Reverse Transcriptase Polymerase Chain Reaction; RNA