Emerging In Vitro Tools to Evaluate Cytochrome P450 and Transporter-Mediated Drug-Drug Interactions

Drug-drug interactions DDI comprise a significant cause of morbidity and mortality worldwide as they may lead to adverse clinical events, result in decrease/inactivation of the therapeutic effect of a drug, may enhance drug toxicity and indirectly compromise treatment outcomes and adherence. Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism, and elimination (ADME). Inhibition or induction of transporter and drug metabolism enzymes can alter the ADME of a co-administered drug, which may lead to drug-induced toxicity or lack of efficacy. This review assesses our current understanding of the in vitro methods of evaluating CYPs and transporter- mediated DDI. The DDI prediction models based on in vitro assays are also discussed in this review. The applications, advantages and limitations of each method are also addressed in this review. Keywords: Drug-drug interaction, drug metabolism enzyme, drug transporters, cytochromes P450, in vitro tools, DDI prediction, ADME, cytochromes, Polypharmacy, Phase 0 metabolism proteins, new chemical entity, NCE, CYP, high pressure liquid chromatography, HPLC, mass spectrometry, Human Liver Microsomes, pseudo 1st order reac-tion, time-dependent inhibi-tion, Mechanism-based CYP inhibition, MBI, NADPH, CYP2D6, CYP3A4, Simple Reversible DDI Prediction Model, DDI, Modified Shift Assay, Multiple Clearance Path-ways, organic anion transporting polypeptides, OATP, multidrug resistance protein 2, MRP2, TDI Prediction Model, CYP1A2, CYP2B6, CYP2C9, CYP2C8, CYP2C19, UGT1A1, HepaRG cells, mitoxantrone re-sistance protein, MXR, P-gp, BCRP, OATPs, OAT, OCT, ATPase assay, NTCP, MDCK, Calcein-AM, HMG-CoA, Caco-2, Cyclosporine A, pregnance X receptor, fexofenadine, rifampin, PXR