CYP Inhibition-Mediated Drug-Drug Interactions

Karoly      Tihanyi; Monika      L. Bakk; Eva      Hellinger; Monika      Vastag

Abstract

Adverse drug reaction is a frequent cause of drug withdrawals from the market. The drug-drug interaction (DDI) potential of new drug candidates is an increasing safety concern of pharmaceutical companies. DDIs frequently occur between coadministered drugs on a pharmacokinetic ground and sometimes create life-threatening conditions. The unexpected increase of the exposure of a drug is most frequently evoked by the inhibition of metabolic enzymes. While the inhibition of CYPs by new drug candidates is unwanted, one has to recognize that several currently marketed successful drugs with relatively clean record of drug-drug interactions are time-dependent inhibitors of drug metabolic enzymes. Therefore, the correct and high throughput prediction of drug-drug interaction propensity of new chemical entities (NCEs) at an affordable cost is a major interest of pharmaceutical research. False negatives and positives, also the misinterpretation of otherwise flawlessly generated data are equally costly or hazardous. While screening methods for the detection of CYP inhibition are available now, the quantitative estimation of DDI potential and its PK effect leaves an ample room for improvement. This is reflected in the great research activity focused on the establishment of correct in vitro-in vivo correlations. The impressing number of recent publications and methods recommended in this field provide an increasingly solid ground for the selection of lead compounds and development candidates.

Keywords: Drug-drug interaction, CYP450, IVIVE, CYPs, of new chemical entities (NCEs), isozymes, cisapride, mibefradil, terfenadine, nefazodone, toxicology, lucocorticoides, biotransformation, Metabolism-based inhibitor (MBI), xenobiotic compounds, CYP monooxygenases, Fluoxetine, paroxetine, fraction metabolized (fm,CYP), conjugases, allosteric feature, Competitive inhibition, metabolite-intermediate complex (MIC), macrolide antibiotics, erythromycin, clarithromycin, troleandomycin, carbamazepine, cyclosporine, midazolam, ritonavir, microsomal monooxygenases, idiosyncratic reactions, Cholestasis, proinflammatory cytokines, antagonize nuclear receptors, ketoconazole, neuropathic pain, poor metabolizer (PM), extensive metabolizer (EM), ultrarapid metabolizer (UM), Ethynyl groups, ethynylestradiol, acetyl salicylic acid, hepatic inlet concentration, metabolite, pregnane X receptor, ultrarapid metabolizer