The present study has demonstrated an interaction between verapamil and grapefruit juice, which is likely due to an inhibition of intestinal metabolism resulting in increased oral bioavailability.
These results suggest that there is no significant interaction between the parent compound quinine and grapefruit juice, so it is not necessary to advise patients against ingesting grapefruit juice at the same time that they take quinine. Since quinine is a low clearance drug with a relatively high oral bioavailability, and is primarily metabolised by human liver CYP3A4, the lack of effect of grapefruit juice on quinine pharmacokinetics supports the view that the site of CYP inhibition by grapefruit juice is mainly in the gut.
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.
Obesity can modify the pharmacokinetics of lipophilic drugs. As quinine is a lipophilic drug, this study was conducted to determine whether the pharmacokinetics of quinine is altered in obese subjects. Nine obese Thai men were compared with 8 age-matched lean men. After an oral dose of quinine had been given to the men, plasma quinine concentrations were measured up to 48 h after the dosing. Mean peak plasma quinine concentration in the obese group was significantly lower than that observed in the controls (4.0 +/- 0.8 vs 5.0 +/- 0.3 mg/L, P < 0.01). There were no significant differences in time to reach the peak plasma concentration, half-life and total clearance of quinine between the 2 groups. The mean clearances of quinine normalized to the ideal bodyweight (IBW) in the obese and the control groups were not significantly different (0.091 +/- 0.018 vs 0.091 +/- 0.024 L/h/kg IBW, P > 0.05). As there are similarities in the total clearance and the clearance of quinine based on IBW, the maintenance dose of quinine should be given to obese patients on the basis of ideal bodyweight, not on total bodyweight.
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