Mechanisms for the uptake of cationic drugs by the liver: a study with tributylmethylammonium (TBuMA).
The mechanisms of hepatic organic cation transport were examined in isolated rat hepatocytes, using the model compound [methyl-3H]tributylmethylammonium (TBuMA). [3H]TBuMA is shown to be taken up into rat hepatocytes by two carrier-mediated systems in addition to a nonsaturable process. The transport mechanisms for TBuMA share common features with both the type I and type II carrier systems reported for exogenous organic cations such as procainamide ethobromide and vecuronium, respectively. Only slight effects were seen in the presence of relatively high concentrations of endogenous organic cations such as thiamine, choline and N1-methyl nicotinamide. The total uptake of [3H]TBuMA was neither influenced by an electronegative membrane potential and variations in external and internal pH, nor by the absence of Na+, K+ or Cl- in the incubation medium. The presence of the inorganic anion I- stimulated the uptake of [3H]TBuMA. An improved presentation or binding to the carrier may be involved because symport with the anion could not be demonstrated. Lowering of the temperature produced a significant reduction in the uptake velocity of [3H] TBuMA, whereas metabolic inhibitors such as valinomycin and carbonylcyanide-m-chlorphenylhydrazone reduced the uptake rate by 80 and 90%, respectively, which was correlated with the extent of ATP depletion. It is concluded that the monovalent cationic drug TBuMA can be considered as a mixed type I/type II compound that exhibits an electroneutral and anion-sensitive uptake mechanism, depending on metabolic energy. The uptake mechanism is dissimilar from Na(+)-dependent and H(+)-dependent transport systems that have been described for endogenous cations, such as thiamine, choline and N1-methylnicotinamide.
Steen
H
H
Department of Pharmacology and Therapeutics, University of Groningen, The Netherlands.
Oosting
R
R
Meijer
D K
DK
D000818:Animals; D001692:Biological Transport; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D004734:Energy Metabolism; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism*; D008564:Membrane Potentials; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics*; D051381:Rats; D013696:Temperature
D000644:Quaternary Ammonium Compounds; C043902:tri-n-butylmethylammonium; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone