Cytochrome P450 3A4 (CYP3A4) is quantitatively the most important P450 enzyme in adults. It is suggested thatCYP3A4genetic polymorphisms may influence the rate of the metabolism and elimination ofCYP3A4 substrates in human beings. Ibrutinib is an anticancer drug and primarily metabolized byCYP3A4. The aim of this study was to systematically investigate the effects of 22CYP3A4 protein variants on the metabolism of ibrutinibin vitro. When compared with wild‐typeCYP3A4.1, two variants (CYP3A4.17 andCYP3A4.24) had no detectable enzyme activity; five variants (CYP3A4.10, .11, .18, .23 and .33) exhibited no significant differences; another five variants (CYP3A4.3, .4, .9, .19 and .34) showed increased intrinsic clearance values, while the remaining nine variants (CYP3A4.2, .5, .14, .15, .16, .28, .29, .31 and .32) displayed decreased enzymatic activities in different degrees. As the first study of 22CYP3A4 protein variants in ibrutinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism and elimination of ibrutinib and also offer a reference to the personalized treatment of ibrutinib in clinic.

Acacetin is a natural flavonoid that is widely distributed in plants and possesses numerous pharmacological activities. The aim of the present study was to investigate the effects of acacetin on the activities of the cytochrome P450 family members CYP1A2, CYP2B1, CYP2C11, CYP2D1, CYP2E1, and CYP3A2 in rat liver microsomes in vitro and rats in vivo to evaluate potential herb-drug interactions by using a cocktail approach. Phenacetin, bupropion, tolbutamide, dextromethorphan, chlorzoxazone, and midazolam were chosen as the probe substrates. An ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous detection of the probe substrates and their metabolites. In vitro, the mode of acacetin inhibition of CYP2B1, CYP2C11, and CYP2E1 was competitive, while mixed inhibition was observed for CYP1A2 and CYP3A2. The Ki values in this study were less than 8.32 μM. In vivo, the mixed probe substrates were administered by gavage after daily intraperitoneal injection with 50 mg/kg acacetin or saline for 2 weeks. The main pharmacokinetic parameters, area under the plasma concentration-time curve (AUC), plasma clearance (CL), and maximum plasma concentration (C_max) of the probe substrates were significantly different in the experimental group than in the control group. Overall, the in vitro and in vivo results indicated that acacetin would be at high risk to cause toxicity and drug interactions via cytochrome P450 inhibition.

CYP2D6 is an important cytochrome P450 (P450) enzyme that metabolizes approximately 25% of therapeutic drugs. Its genetic polymorphisms may significantly influence the pharmacokinetics and pharmacodynamics of clinically used drugs. Studying the effects of CYP2D6 on drug metabolism can help reduce adverse drug reactions and therapeutic failure to some extent. This study aimed to investigate the role of CYP2D6 in nebivolol metabolism by evaluating the effect of 24 CYP2D6 variants on the metabolism of nebivolol in vitro. CYP2D6 variants expressed by insect cell systems were incubated with 0.1–80 μM nebivolol for 30 minutes at 37°C and the reaction was terminated by cooling to −80°C immediately. An ultra-performance liquid chromatography–tandem mass spectrometry system was used to analyze nebivolol and its metabolite 4-hydroxy nebivolol. Compared with CYP2D6.1, the intrinsic clearance values of most variants were significantly altered, and most of these variants exhibited either reduced V_max and/or increased K_m values. Variant R440C showed much higher intrinsic clearance than the wild type (219.08%). Five variants (CYP2D6.88, CYP2D6.89, R344Q, V342M, and D336N) exhibited no difference from the wild type. CYP2D6.92 and CYP2D6.96 displayed weak or no activity, whereas the intrinsic clearance values of the remaining 16 variants were significantly reduced to various degrees (ranging from 4.07% to 71%). As the first report of 24 CYP2D6 alleles for nebivolol metabolism, these results are valuable to interpreting in vivo studies and may also serve as a reference for rational clinical administration.

Chiral metabolism of propafenone in rat hepatic microsomes treated with two inducers