In vitro hepatic metabolism of CYP3A‐mediated drugs quinine and midazolam in the common brush‐tailed possum (Trichosurus vulpecula)

Abstract

Abstract-This report characterizes the P450 isoenzymes involved in quinine metabolism in liver microsomes of the common brush-tailed possum (Trichosurus vulpecula). The mean maximal velocity (V max ) for 3-hydroxyquinine formation in possum livers was 1,512 Ϯ 510 pmol/mg protein/min (males) and 1,680 Ϯ 690 pmol/mg protein/min (females). The mean V max value for 3-hydroxyquinine formation in possums was approximately threefold higher than that found in human livers. The mean apparent Michaelis constant (K m ) for 3-hydroxyquinine formation in possum livers was 31.9 Ϯ 16 M in males and 16.1 Ϯ 5 M in females. At low concentrations of quinine (40 M), the quinine 3-hydroxylation was inhibited more than 90% by midazolam, 60% by troleandomycin, 40% by erythromycin, and 47% by nifedipine, all of which are CYP3A inhibitors. Other inhibitors for CYP2C9/ 10, CYP2D6, CYP2E1, and CYP1A1/2 showed little or no inhibition effect on 3-hydroxylation of quinine. Xenobiotic inhibition studies suggest that the liver CYP3A enzyme family or one similar to human liver CYP3A is responsible for 3-hydroxylation of quinine in possum livers. The metabolism of midazolam to 1Ј-hydroxy and 4-hydroxy metabolites was also studied. The in vitro metabolism of midazolam was found to be much lower in possum liver microsomes as compared to that observed in human liver microsomes. The mean V max values for 4-hydroxy-and 1Ј-hydroxymidazolam in male possums were 179 Ϯ 53 and 479 Ϯ 333 pmol/mg protein/min, respectively. For female possums, the mean V max values were 235 Ϯ 31 and 671 Ϯ 143 pmol/mg protein/ min, respectively. These V max values for male possums were 23 and 8 times less (17 and 6 times less for female possums), respectively, than those observed with human liver microsomes. The present study has demonstrated that, although possums are able to metabolize both midazolam and quinine, the capacity to metabolize midazolam is considerably lower in possum livers than in human livers. This finding could be useful for the selection of alternative poisons to control populations of possums.

In Vitro Hepatic Assessment of Cineole and Its Derivatives in Common Brushtail Possums (Trichosurus vulpecula) and Rodents

“…Although CYP3A is involved in the metabolism of plant secondary metabolites, other studies have reported that possums depend to a lesser extent on CYP3A than other species. This was evident when the metabolism of midazolam, a specific substrate of CYP3A, in possum liver was lower than that reported in human liver [ 12 ]. Specifically, the V max values ( p mol/mg/min) of 4-hydroxymidazolam and 1′-hydroxylmiazolam in possum liver microsomes were 23- and 8-fold lower than those observed in human liver microsomes.…”

Antimalarial interaction of quinine and quinidine with clarithromycin

“…To resolve these and to prolong the life of existing drugs it is necessary to devise new combinations based on the PK-PD properties of the partner drugs (Wongsrichanalai et al 2002; Sidhu et al 2005). These two drugs (QN/QND) are metabolized in the liver mainly by CYP3A4 (Ho et al 1998; Nielsen et al 1999). During uncomplicated malaria, bioavailability of these antimalarials decreases significantly below a therapeutic level.…”