PT  - JOURNAL ARTICLE
AU  - Junko Ishizaki
AU  - Koichi Yokogawa
AU  - Fujio Ichimura
AU  - Shoji Ohkuma
TI  - Uptake of Imipramine in Rat Liver Lysosomes In Vitro and Its Inhibition by Basic Drugs
DP  - 2000 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1088--1098
VI  - 294
IP  - 3
4099  - http://jpet.aspetjournals.org/content/294/3/1088.short
4100  - http://jpet.aspetjournals.org/content/294/3/1088.full
SO  - J Pharmacol Exp Ther2000 Sep 01; 294
AB  - We investigated the uptake of imipramine (IMP) in highly purified lysosomes from rat liver and its inhibition by a variety of basic drugs in vitro. The uptake of [3H]IMP into lysosomes peaked in less than 20 s, showing little temperature dependency or countertransport phenomena. It was accelerated by increase of extralysosomal pH, stimulated by Mg2+-ATP in KCl buffer, and suppressed by acidic ionophores. However, the uptake of [3H]IMP in lysosomes was approximately 140-fold higher than the value expected from the pH-partition theory. IMP and other weak lipophilic bases like chlorpromazine and propranolol raised the intralysosomal pH, and their potency was stronger than that of NH4Cl, a typical pH-perturbing weak base. A variety of basic drugs inhibited the uptakes of [3H]IMP and [14C]methylamine into lysosomes, their 50% inhibitory concentrations (IC50) being almost the same for [3H]IMP and [14C]methylamine uptake (r = 0.842). A high correlation (r = 0.946) was observed between the IC50 values (for the inhibition of [3H]IMP uptake) and the lipophilicity (Poct values). These results suggest that the accumulation of lipophilic basic drugs is driven primarily by the transmembrane pH difference (pH-partition theory) but with the involvement of some additional mechanism(s) related to drug lipophilicity, possibly binding (partition or adsorption) to lipophilic substance(s) and/or aggregation within lysosomes. Based on this idea, we have established a model that described and successfully simulated the weak base-induced pH increase, the accumulation of a lipophilic weak base (IMP), and the inhibition of accumulation of IMP by lipophilic basic drugs. The American Society for Pharmacology and Experimental Therapeutics