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and time‐dependent inhibition of enzymes 1CYPs UGT1A1 UGT2B7 CYP3A4, CYP2C9 CYP2C19 UGT2B7 — — Induction of enzymes CYP1A2 CYP2B6 CYP3A4 2CYP2C CYP3A4 — — Transporters Inhibition of uptake transporters OATP1B1 OATP1B3 OCT1 OCT1 OAT1 OAT3 OCT2 — Inhibition of efflux transporters P‐gp BCRP 3MRP2 P‐gp BCRP 3MRP2 P‐gp BCRP MATE1 MATE2/K 3MRP2 3MRP4 P‐gp BCRP

      The rationale for the significance of enzymes and transporters presented in Table 2.1 are as follows:

       High affinity, low‐capacity enzymes like CYPs 2C9, 2C19, and 2D6 are more susceptible for inhibition.

       Polymorphic enzymes (CYPs 3A5, 2B6, 2C8, 2C19, 2D6; UGTs 1A1, and 2B7) when involved in DDI could contribute to exaggerated exposure variability in some patients.

       Enzymes that are expressed in gut (CYP3A4, UGT2B7, etc.) are exposed to higher perpetrator concentrations during absorption phase and therefore contribution of the gut to the overall DDI risk is considerably high.

       Clinically relevant DDIs are rare for UGTs, as many of them are low‐affinity, high‐capacity enzymes with broad substrate specificity. Most interactions involving UGTs are associated with low AUC ratios and mostly confined to UGT2B7, a polymorphic enzyme that is involved in the metabolism of many marketed drugs.

       Among transporters, organic anion transporting protein (OATP1B1 and OATP1B3), organic cation transporters (OCT1, OCT2), P‐glycoprotein (P‐gp), and breast cancer resistance protein (BCRP) are polymorphic.

       Many statins rely on OATP1B1 for their uptake into liver. They are likely to be victims of DDI, when coadministered with OATP1B1 inhibitors. Due to their widespread use, high probability of comedication, and the risk of myalgia and rhabdomyolysis with increased exposure, statins attract considerable interest with respect to DDI.

       Among the efflux transporters, interactions with P‐gp are the most studied. Inhibition of P‐gp may not result in clinically significant differences in the exposure of the victim drug, but it can attenuate the efficacy of drugs targeting barrier tissues such as brain, lymphocytes, and tumor.

Schematic illustration of perpetrator and victim properties impacting drug interaction risk.

      Induction and/or inhibition of drug transporters of the small intestine, liver, and kidney are major determinants of drug–drug interactions. Transporter‐mediated drug–drug interactions in these three organs can considerably influence the pharmacokinetics and clinical effects of drugs. Transporters of interest are those controlling intestinal efflux, hepatic efflux, blood–brain barrier (P‐gp and BCRP), hepatic uptake (OATP1B1 and OATP1B3) and renal tubular uptake/bidirectional transport (OAT1, OAT3, OCT2), and efflux (MATE1 and MATE2/K). Renal DDIs are rare and associated with significantly lower AUC ratios compared with hepatic DDIs. Victims of renal DDIs are generally compounds whose eliminations are largely dependent on the renal route. Examples include metformin, a substrate of OCT2 and MATEs, and the endogenous compound creatinine, a substrate of OAT2, OCT2, and MATEs, the secretion of both of which are reduced by cimetidine, known to inhibit OCT2 and MATEs. Cimetidine also reduces the renal clearance of bisoprolol, nicotine, and procainamide (Ayrton and Morgan, 2001; Shitara et al., 2009; Shitara et al., 2009; Kirch et al., 1987; Somogyi et al., 1987; Bendayan et al., 1990; Ayrton and Morgan, 2001; Shitara et al., 2009; Ivanyuk et al., 2017). Uptake transporters act in concert with efflux transporters to eliminate toxins (e.g., OCT2 and MATE1, MATE2‐K). Therefore, for secreted drugs that are reliant on transporters for overcoming the membrane barrier, the inhibition of efflux transporters could result in an accumulation of drugs in the cytoplasm of proximal

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