Kovid's portable calibre doesn't recognize drive letter changes?
Well, I suppose that is one good reason why I like the PortableApps.com version.
PortableApps.com can set the current drive letter and apply it to any app that asks for it -- it works flawlessly.
Just install the PortableApps.com launcher (if you are using portable software, this is a must-have) and install their calibrePortable from here:
http://portableapps.com/node/20518