Abstract

GF120918A, the HCl salt of GF120918 (9,10-dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl) ethyl]phenyl]-4-acridine-carboxamide), has been used both in vitro and in vivo as a tool inhibitor of P-glycoprotein (Pgp) to investigate the role of transporters in the disposition of various test molecules. However, to date, a detailed description of the preclinical pharmacokinetic properties of GF120918A has not been published. This investigation was performed to evaluate in vitro and in vivo pharmacokinetic properties of GF120918A in the mouse, rat, dog, and monkey and to evaluate the in vivo efficacy of GF120918A in modulating absorption and systemic exposure in the monkey. GF120918A demonstrated reasonable absorption and systemic exposure in each of the species studied, however, in rodents, administration of 300 mg/kg afforded a substantially less than linear increase in systemic exposure compared with 30 mg/kg. In accordance with its intestinal and hepatic exposure and potency against P-glycoprotein, GF120918A demonstrated marked modulation of erythromycin systemic exposure in the monkey, with no effect on propranolol, a negative control molecule. In vitro, GF120918A demonstrated high plasma protein binding across species, although a definitive protein binding evaluation was precluded by poor recovery, particularly in buffer and in mouse, rat, and dog plasma. GF120918A did not demonstrate potent inhibition of several human cytochrome P450 enzymes evaluated in vitro, with IC₅₀ values well above concentrations anticipated to be achieved in vivo. Together, these data confirm the utility of GF120918A as a tool P-glycoprotein inhibitor in preclinical species and offer additional guidance on preclinical dose regimens likely to produce P-glycoprotein-mediated effects.