By closing the hatches that connect the four main modules - two Russian and two American - and monitoring them independently, the space agencies of both nations hope to narrow their search for the presumed leak.
While Russia insists the leak has stabilised, NASA said it continued to cost the station 1-1/2 to 3 pounds of air a day.
"Americans know their systems well and Russian academics know their systems and therefore they need to be separated to see where the pressure loss is occurring, in which section of the station," Vyacheslav Mikhailichenko, spokesman for Russian space agency Rosaviakosmos, told Reuters on Friday.
The astronauts, Michael Foale and Alexander Kaleri, would be confined on Wednesday to the Russian Zvezda module, where their Russian Soyuz escape capsule is docked.
That would halt all their science work and separate them from most of the communication equipment on the station located in the US Destiny laboratory module.
"Since that's [Zvezda module] where the (carbon dioxide) scrubbing systems are, and the potty and the galley, the crew will have to reside in there. They'll probably have to stay in this isolated state for four or five days," said space station operations integration manager Mike Seffredini at NASA.
The module is designed for two, so comfort is no issue.
But they will be suspending operations on the very day US President George Bush is expected to announce the future of the space station in a major policy address on space flight.
The station has numerous critics who argue it has demonstrated no real scientific merit since orbital assembly began in 1998, is too costly, at $95 billion, and is in constant need of repair.
Defenders compare it to national laboratories, which rarely announce headline-grabbing discoveries, but daily contribute to the ongoing work of science.
What is beyond doubt is that the project is four years behind schedule, in part because the US shuttle fleet has been grounded since February 2003 after Columbia broke apart, but also because of Russia's money woes.
Russia has assumed full responsibility for launching manned and cargo ships to keep the station in orbit, but modules belonging to NASA's other international partners remain in storage at the Kennedy Space Centre in Florida.
Both NASA and Rosaviakosmos say the space station crew are in no danger.
But the Russians and their US partners disagree on the amount of air being lost.
Mikhailichenko said there had been a decline in pressure between 31 December and 5 January and it had now stabilised. NASA says the fall started on 22 December and is continuing, but at about half the rate it was.
"Today we can establish the fact that the pressure is within a normal range," Mikhailichenko said, adding small weekly fluctuations were normal and depended on oxygen and humidity levels and other factors.