Human accumulation potential of xenobiotics: potential of catamphiphilic drugs to promote their accumulation via inducing lipidosis or mucopolysaccharidosis.
1. Drug accumulation without a concomitant elevation of blood level may occur if the capacity of the tissue to bind drug increases during chronic treatment. 2. This special type of accumulation is found with cationic-amphiphilic drugs, which induce the formation of lysosomal inclusion bodies containing undergraded lipids or mucopolysaccharides (drug-induced lipidosis or mucopolysaccharidosis, respectively); the stored material provides the additional binding sites for the drug. 3. Factors determining the potential for inducing lipidosis or mucopolysaccharidosis are: (a) affinity of the drugs to phospholipid layers (governed by hydrophobicity) or mucopolysaccharides (drug-induced lipidosis or mucopolysaccharidosis, respectively); the free intra-lysosomal concentration, which is elevated compared with the blood level due to lysosomal trapping (especially with dicationic drugs); (c) the therapeutically required drug concentration in the blood: the therapeutic concentrations are high with drugs that do not act via binding to specific high-affinity receptors.
Hein
L
L
Department of Pharmacology, University of Kiel, FRG.
Lüllmann-Rauch
R
R
Mohr
K
K
D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008064:Lipidoses / Q000139:chemically induced* / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D009083:Mucopolysaccharidoses / Q000139:chemically induced* / Q000378:metabolism; D014018:Tissue Distribution; D015262:Xenobiotics / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D006025:Glycosaminoglycans; D015262:Xenobiotics