If your fuel tank is set at the right level it makes no difference which way your 2-strike is oriented. But you have to remember that the fuel tank level that's best for an upright engine is not the same as for an inverted engine. Best method is trial and error. I set up my old Thundertiger Champion 45L by flipping the plane upside down and right side up until there was virtually no RPM change either way and never had a flameout. Only took about 45 minutes.

Not sure about 4-strokes, though. No experience with them being inverted.