Postnatal development of organic cation transport in the rat liver

Previous studies have demonstrated that the small permanently charged organic cation 1-methyl-4-phenylpyridinium (MPP+) is avidly taken up by rat hepatocytes. The aim of this study was to characterise the postnatal development of hepatic uptake of organic cations, using the model compound MPP+. Accumulation of [3H]MPP+ by liver slices obtained from rats ranging from 1 day to 7 weeks was measured, and the effect of a series of compounds on [3H]MPP+ uptake was examined. The accumulation of [3H]MPP+ by liver slices was similar in adult (87.5 +/- 19.9 pmol g-1; n = 7) and neonatal rats (110.6 +/- 11.5 pmol g-1; n = 15). Verapamil, quinidine (100 microM) and progesterone (200 microM) produced very marked reductions on [3H]MPP+ uptake at all ages, and the inhibitory effect of verapamil and quinidine was maximum in livers from 1-day-old rats. Bilirubin (200 microM) significantly reduced [3H]MPP+ uptake by liver slices from 1 day, 1 week and 7-week-old rats. However, [3H]MPP+ accumulation was reduced by cimetidine, vinblastine and daunomycin (100 microM) in 1-day-old rats, but the effect of these drugs disappeared as the animals age increased. These findings demonstrate that hepatic organic cation uptake capacity is remarkably high shortly after birth and suggest that at least two distinct uptake mechanisms are involved in this process. These uptake systems are the type I hepatic transporter of organic cations, active from birth to adulthood, and P-glycoprotein, active only in very young rats.