Zamicastat is an inhibitor of dopamine β-hydroxylase (DBH), and is also a concentration-dependent dual inhibitor of P-gp and BCRP(IC50 values of 73.8 μM and 17.0 μM, respectively).
Zamicastat (10, 30 and 100 mg/kg/day; oral bolus, 7 days) is tested acutely against salt-induced hypertension in the Dahl SS rat. Zamicastat produces a dose-dependent decrease in blood pressure. 24 h after Zamicastat administration mean systolic blood pressure (SBP) decrease is-12.6±4.1 mm Hg (P = 0.0284),-15.2±2.7 mm Hg (P = 0.0026) and-19.0±3.7 mm Hg (P = 0.0036) for the 10, 30, and 100 mg/kg body weight dose, respectively. Zamicastat administration also produces a significant 24-h average decrease in diastolic blood pressure (DBP) of-14.6±3.4 mm Hg (P = 0.0073) with 10 mg/kg body weight dose,-13.0±4.5 mm Hg (P = 0.0347) with 30 mg/kg body weight dose and-15.0±3.1 mm Hg (P = 0.0046) with 100 mg/kg body weight dose. Zamicastat administration leads to a decrease in the 24h post-dose mean arterial pressure (MAP) of-13.4±3.8 mm Hg (P = 0.0162),-14.0±3.5 mm Hg (P = 0.0101) and-20.6±3.7 mm Hg (P = 0.0026) for the 10, 30, and 100 mg/kg body weight dose, respectively. There is a small, but significant, effect of Zamicastat on the 24-h mean heart rate (HR) post-dose for all tested doses (10 mg/kg:-19.1±3.2 beats/min, P = 0.0019; 30 mg/kg:-13.0±4.5 beats/min, P = 0.0347; 100 mg/kg:-21.6±6.6 beats/min, P = 0.0235). Animal model: Six-week-old male inbred male Dahl SS rats. Dosage: 10, 30, or 100 mg/kg; 4 mL/kg. Administration: Oral bolus, daily, seven days. Result: Treatment produced a dose-dependent decrease in blood pressure. Twenty four hours after administration mean SBP decrease was-12.6±4.1 mm Hg (P = 0.0284),-15.2±2.7 mm Hg (P = 0.0026) and-19.0±3.7 mm Hg (P = 0.0036) for the 10, 30, and 100 mg/kg body weight dose, respectively. Animal model: ten-week-old male Wistar Han rats. Dosage: 30 mg/kg/day. Administration: in animal feedings (mixed in meal rodent food) everyday. Result: lead to a significant 51% decrease in noradrenaline levels excreted in urine.
In Vitro
Following 4 hours of incubation (5, 10, 20, 50, 80, 100 μM), a significant loss of cell viability is verified with 100 μM Zamicastat (p=0.010) in MDCK-BCRP cells. No significant losses of cell viability are observed after 4 h of incubation for other concentrations in all cell lines. By decreasing the incubation period to 30 min, there is no significant loss of cell viability (p>0.05) at 100 μM in all cell lines. Cell Viability Assay Cell line: MDCK II, MDCK-MDR1 and MDCK-BCRP cells. Concentration: 5, 10, 20, 50, 80, 100 μΜ. Incubation time: 4 hours (5, 10, 20, 50, 80, 100 μM) or 30 min (only 100 μM). Result: A significant loss of cell viability was verified with 100 μM in MDCK-BCRP cells.
1 mg, 5 mg, 10 mg, 50 mg, 25 mg, 100 mg, 1 ml x 10 mM (in DMSO)
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