Jack Wilshere and Andy Carroll have been left out of England's Under-21 squad for the European Championship finals in Denmark this summer.
Arsenal boss Arsene Wenger was strongly against Gunners midfielder Wilshere, 19, being included in the squad.
"I spoke to Jack last week," said U21 boss Stuart Pearce.
"He explained that while he told me in March that he wanted to be part of the squad, he now feels he is not in the best condition to take part."
Pearce added: "That is based on the number of games he has played for Arsenal this season, sports science data which Jack was presented with last week and concerns he has for his fitness looking ahead to next season.
"Jack has always expressed his enjoyment at being involved with the Under-21 squad and while I am disappointed not to have him with us for the finals I've accepted the situation."
Liverpool striker Carroll, who missed his club's final game of the Premier League season on Sunday, has been left out because of injury and the absence of both players will be a blow for Pearce.
The U21s coach had named Wilshere and Carroll in his initial 40-man squad and Wenger even stated ahead of the expected squad announcement on 19 May that Wilshere had been picked for the final 23-man squad going to Denmark.
But, after Pearce postponed naming his squad until Monday, Wilshere has instead been named in the full England squad to play Switzerland on 4 June.
Wenger was concerned about the potential for the PFA Young Player of the Year to suffer burnout, with the youngster having played 48 games for Arsenal this season and establishing himself in England manager Fabio Capello's full side, for whom he has won four caps.
"He has played nearly 50 games this year [for Arsenal]. To go to a tournament, for me, is a massive risk," Wenger said last Thursday.
"I am happy if the Under-21s do well because I want England to do very well.
"Jack knows that he is nearly at the end of his energy level but he is keen to do well."
But Pearce said: "I am very conscious of the importance of looking after all our players, and that is why I have frequent conversations with club managers throughout the season.
"I believe that representing your country in international development tournaments can be a great advantage to players, and increases the chances of being successful at senior level."
The situation regarding Carroll, who has not been picked by Capello to play Switzerland, resulted in the forward starting in Liverpool's penultimate game of the campaign against Tottenham but missing out altogther for the last game of the seaon at Aston Villa.
He has struggled with injury since his £35m move to Liverpool from Newcastle in January and made just six starts in nine outings for the Reds, with the Merseysiders likely to welcome a summer of rest for their player.
Despite losing the services of Carroll and Wilshere, Pearce has been able to draw on the experience of four full internationals in the shape of Manchester City defender Micah Richards, Arsenal full-back Kieran Gibbs, Sunderland midfielder Jordan Henderson and Manchester United striker Danny Welbeck.
England's campaign at the European Championships will begin on 12 June against Spain before they play Ukraine three days later.
They finish their Group B fixtures on 19 June against Czech Republic, with the semi-finals and final taking place the following week.
England Under-21 squad
Frankie Fielding (Derby County), Jason Steele (Middlesbrough), Alex McCarthy (Reading)
Ryan Bertrand (Chelsea), Kieran Gibbs (Arsenal), Phil Jones (Blackburn Rovers), Michael Mancienne (Chelsea), Micah Richards (Manchester City), Chris Smalling (Manchester United), Kyle Walker (Tottenham Hotspur)
Marc Albrighton (Aston Villa), Tom Cleverley (Manchester United), Jack Cork (Chelsea), Jordan Henderson (Sunderland), Henri Lansbury (Arsenal), Fabrice Muamba (Bolton Wanderers), Jack Rodwell (Everton), Danny Rose (Tottenham Hotspur), Scott Sinclair (Swansea City)
Nathan Delfouneso (Aston Villa), Daniel Sturridge (Chelsea), Danny Welbeck (Manchester United), Connor Wickham (Ipswich Town)