Pavinetant (MLE-4901)

Kinase experiment:

The potential of Pavinetant (AZD2624) to cause time-dependent inhibition of CYP3A activities is evaluated by pre-incubating 10 μM of Pavinetant at 37°C for 0, 3, 10, 20, and 30 min in 0.1 M pH 7.4 phosphate buffer incubation mixture (0.2 mL) containing 2 mg/mL HLM and 1 mM NADPH. Verapamil, tested at 10 μM, is also incubated separately as a positivecontrol. An aliquot of 20 μL is removed from pre-incubation tube at each time point and added to a secondary 5-min incubation(180 μL) containing 15 μM of midazolam and 1 mM of NADPH. The formation of 1′-hydroxymidazolam is used as the marker activity for CYP3A enzymes and analyzed using LC-MS. CYP3A enzyme activities after pre-incubation with Pavinetant arecompared to activities following incubation with vehicle solvent (1% methanol) and without pre-incubation[1].

References:

[1]. Li Y, et al. In vitro assessment of metabolic drug–drug interaction potential of AZD2624, neurokinin-3 receptor antagonist, through cytochrome P(450) enzyme identification, inhibition, and induction studies. Xenobiotica. 2010 Nov;40(11):721-9.