Whole body distribution of the quaternary ammonium compound thiazinamium (N-methylpromethazine) and promethazine in monkey and mice

Abstract

The distribution of 35S-ringlabeled thiazinamium (N-methyl-promethazine) methylsulphate (35S-Th.) and its tertiary analog 35S-promethazine hydrochloride (35S-Pr.) have been studied by means of whole body autoradiography in a squirrel monkey and in mice. After infusion of 35S-Th. in the monkey until steady state condition, high accumulations of radioactivity were found in the three main organs of excretion of the drug (liver, kidneys and intestines). High concentrations of radioactivity were also observed in organs with high amounts of acetylcholine receptor such as the ganglia, skeletal muscles, myocard and ciliary bodies, and in glandular tissue such as salivary glands, thyroid gland and pancreas. On the other hand no radioactivity was seen in the central nervous system with exception of the posterior pituitary gland and the fourth ventricle. This suggests that Th.-cations cannot pass "the blood-brain barrier", except for some high permeability regions that are known to be "windows" in this barrier. 35S-Pr. was distributed significantly different. Now a high level of radioactivity was seen in the central nervous system, indicating that the tertiary amine compound can easily pass "the blood-brain barrier". Again high concentrations of radiation were found in liver, kidneys and intestines. 35S-Pr. also seemed to penetrate to acetylcholine receptor areas. Substantial accumulation in the eye was seen, as well as in glandular tissues. Essentially the same distribution patterns as described above were seen for 35S-Th. and 35S-Pr. after intramuscular injection in mice. In pregnant mice, after administration of 35S-Th. high concentration of radioactivity was found in the placenta, but only low amounts were seen in the foetus, and then only in the liver and the kidneys, which implies that Th.-cations can pass the placenta, however, to a low extent and at a low rate. With 35S-Pr. obviously placenta transfer can occur more easily and distribution in the foetus is not restricted to the liver and kidneys.