Subject(s)
Misonidazole/analogs & derivatives , Radiation-Sensitizing Agents/adverse effects , Adult , Aged , Clinical Trials as Topic , Humans , Kinetics , Middle Aged , Misonidazole/adverse effects , Misonidazole/blood , Misonidazole/metabolism , Nausea/chemically induced , Radiation-Sensitizing Agents/blood , Radiation-Sensitizing Agents/metabolism , Vomiting/chemically inducedABSTRACT
The mixed-function radiosensitizer RSU-1069 and its analogues possess both alkylating and electron-affinic properties, and have been shown to be more efficient radiosensitizers than misonidazole both in vivo and in vitro. The pharmacokinetics following intraperitoneal injection of three members of this series, RSU-1069, RSU-1164, and RSU-1172 have been studied in C57BL mice bearing B16 melanoma. Peak tumor levels of each compound, and tumor/plasma ratios (T/P) were found to be high: T/P RSU-1069 = 3.8, RSU-1164 = 3.7; RSU-1172 = 4.0. In contrast, other normal tissues including brain showed tissue/plasma ratios close to 1. The mechanisms responsible for differential tumor uptake are unknown, but may depend on the basicity of the compounds, leading to preferential uptake in areas of low pH, or alternatively they may be associated with the alkylating function. This group of compounds appear to demonstrate highly favorable tissue distributions.
Subject(s)
Melanoma/metabolism , Misonidazole/analogs & derivatives , Radiation-Sensitizing Agents/metabolism , Animals , Male , Mice , Mice, Inbred C57BL , Misonidazole/blood , Misonidazole/metabolism , Neoplasm Transplantation , Radiation-Sensitizing Agents/bloodABSTRACT
The enzyme phenylalanine ammonia lyase taken orally has been found to reduce the rise in blood phenylalanine that normally occurs following a protein meal. Therefore the enzyme has a potential use in the management of the genetic disease phenylketonuria. The enzyme mediates the conversion of phenylalanine to cinnamic acid and its possible clinical future has necessitated a more detailed study of the product of its reaction. Cinnamic acid is a compound of low toxicity which is converted in the mammalian body primarily to hippuric acid. We have examined the kinetics of this process in a healthy male and in two patients with untreated phenylketonuria. In addition we have attempted to clarify the inconsistencies in earlier published work about the status of other, minor metabolites. Following an oral load of sodium (2H6) cinnamate there is an increase in urinary hippuric acid largely due to the excretion of (2H5) hippuric acid. In the subjects studied there was no major difference in the rate of elimination although the amount of cinnamic acid converted was less in those with phenylketonuria. This may reflect reduced first-pass absorption by the liver in untreated phenylketonuria enabling increased uptake to occur in other parts of the body.
