Defoe was substituted 20 minutes from time at West Brom on Wednesday night and now Santini is considering leaving him out from the start against Steve Bruce's side on Saturday.
"We will look at Jermain again before deciding whether he plays against Birmingham," the Spurs boss said.
"It's natural for him to be tired. He's played three games for us and came on for England last week.
"We spent three hours on the coach coming back from West Brom so everyone in the squad is feeling a little fatigued."