Influence of ammonium chloride on the tissue distribution of anticholinergic drugs in rats

Ammonium chloride (NH4Cl) increases lysosomal pH and thereby abolishes intr alysosomal accumulation of drugs. Its effect on the tissue distribution of biperiden and trihexyphenidyl in rats has been investigated. The tissue-plasma concentration ratios (K-p) of these drugs in various tiss ues were determined by infusion studies at steady-state in the presence or absence of NH4Cl. Treatment with NH4Cl reduced the K-p values for both drug s, causing the largest reduction in K-p in the lung (52.1 to 11.8 for biper iden and 59.5 to 18.9 for trihexyphenidyl; ratios of decrease 0.77 and 0.68 , respectively), followed by the heart and kidneys, with relatively small r eductions in the brain, gut, muscle and fat. Subcellular fractionation stud ies in the lung indicated that the subcellular fraction-plasma concentratio n ratio of each drug at the steady state (K-p,K-sf) was reduced by treatmen t with NH4Cl, with the largest decrease in the post-nuclear fraction (ratio of decrease 0.82 for biperiden and 0.74 for trihexyphenidyl), followed by the nucleus, microsomes and supernatant, in that order. A strong correlatio n was found between the ratio of decrease in K-p,K-sf after NH4Cl treatment and the specific activity of acid phosphatases, a marker of lysosomes, in each fraction (biperiden, r = 0.948; trihexyphenidyl, r = 0.945). These results suggest that acidic organelles contribute significantly to th e distribution kinetics of anticholinergic drugs.