If your objective is to upload different EPUBs to different distributors because they want different cover image sizes, then yes, you should save to disk for one distributor and then switch the cover in calibre and resave.
Note: I don't really know a lot about selling ebooks, so I have no idea whether that is something the distributors want, but if you say that's what you are trying to do then
Note2: When selling on Amazon, it is best to use the official Amazon-blessed KindleGen on the final version of your EPUB rather than using calibre. Amazon has been known to throw hissy fits when it senses that you used calibre.
Also, Amazon only accepts dual-MOBI (or old MOBI?) which is the native output of KindleGen. calibre creates old MOBI and new AZW3, so if you want to make sure your customers get the best (AZW3) experience you should upload a KindleGenned dual-MOBI. You can also upload an EPUB and Amazon will convert it for you.
Note3: Amazon requires a separately uploaded cover image anyway.