title: Contribution of lysosomes to the subcellular distribution of basic drugs in the rat liver.
abstract: OBJECTIVE
  We examined the subcellular distribution of the basic drugs, chlorpromazine (CPZ), imipramine (IMP) and biperiden (BP), in rat liver, and evaluated the contribution of lysosome (Lys) to their intracellular distribution in comparison with that of mitochondria (Mit).
  
  
  METHODS
  In an in vivo distribution, the concentrations of CPZ, IMP and BP in the liver subcellular fractions were determined. In an in vitro study, uptake of [3H]IMP into Lys and Mit fractions was determined in the presence or absence of several agents.
  
  
  RESULTS
  The distribution of these drugs 10 min after administration was quite similar. However, the relative specific contents (the drug concentration per protein of each fraction divided by that of the total homogenate) in Lys were 7.3, 9.6 and 4.2, respectively for CPZ, IMP and BP, whereas those in the other organella were only 0.4 approximately 1.7. In an in vitro uptake study, the dose response of IMP uptake into Lys was biphasic, while that into Mit fractions was monophasic. The binding of IMP to the high affinity sites of Lys was pH dependent and disappeared in 50 mM NH4Cl or 50 microM CPZ, both of which increased the intralysosomal pH, the low affinity sites were not affected by these drugs.
  
  
  CONCLUSIONS
  The results indicated that Lys has the highest affinity for the basic drugs in the liver and that its contribution to their subcellular distribution depends on the intralysosomal pH, which is also affected by these drugs. The importance of these effects may become significant in combination therapy using various basic drugs.
authors.affiliation: Hospital Pharmacy, Kanazawa University, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Ishizaki
authors.forename: K
authors.initials: K
authors.lastname: Yokogawa
authors.forename: M
authors.initials: M
authors.lastname: Hirano
authors.forename: E
authors.initials: E
authors.lastname: Nakashima
authors.forename: Y
authors.initials: Y
authors.lastname: Sai
authors.forename: S
authors.initials: S
authors.lastname: Ohkuma
authors.forename: T
authors.initials: T
authors.lastname: Ohshima
authors.forename: F
authors.initials: F
authors.lastname: Ichimura
mesh_terms: D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000493:pharmacokinetics; D000978:Antiparkinson Agents / Q000493:pharmacokinetics; D014150:Antipsychotic Agents / Q000493:pharmacokinetics; D001712:Biperiden / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002746:Chlorpromazine / Q000493:pharmacokinetics; D003911:Dextrans; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D007099:Imipramine / Q000493:pharmacokinetics; D007476:Ionophores / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D015388:Organelles / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000378:metabolism*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D003911:Dextrans; D007476:Ionophores; C015219:fluorescein isothiocyanate dextran; D001712:Biperiden; D016650:Fluorescein-5-isothiocyanate; D007099:Imipramine; D002746:Chlorpromazine