Читать книгу Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters - Страница 51

The DDI mechanisms and the enzymes and transporters at various sites recommended for DDI risk assessment by FDA and EMA are summarized in Table 2.1.

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.