Drug-drug interactions of anti-infective drugs: utility of fluorescence cyp inhibition assays in drug discovery.
Drug interactions are often a result of induction or inhibition of cytochrome P450 (CYP) enzymes by co-administered drugs. A high throughput fluorescence assay using cDNA-expressed human CYP isozymes and fluorogenic substrates has been reported for the study of CYP inhibition. We used this assay to evaluate CYP inhibition profiles of 21 marketed anti-infective drugs. We found that six of the eight potent inhibitors identified in this screen (IC50 <10 microM against at least one CYP isozyme) correlated with significant drug-drug interactions in the clinic. In contrast, the intermediate and weak inhibitors (IC50 >10 microM) did not indicate clinically significant drug interactions. Furthermore, we observed that results obtained in the fluorescence assay correlated with conventional, well-established, low throughput methods that utilize human liver microsomes. These data suggest that in the early stages of drug discovery, the fluorescence assay for CYP inhibition could be used in conjunction with a human liver microsomal assay to identify new chemical entities with a potential for drug-drug interactions.
Fridén
Markus
M
Department ofPharmacokinetics and Drug Metabolism, AstraZeneca Mölndal, Mölndal, Sweden.
Vanaja
K
K
Nandi
Vrinda N
VN
D000890:Anti-Infective Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D004008:Diclofenac / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology
D000890:Anti-Infective Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007527:Isoenzymes; D004008:Diclofenac; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases