Murray and Skupski lost in straight sets to the home pair, who put in a commanding performance to win 6-3, 6-4 in Tokyo.
McLachlan and Nishikori started the match brightly and they soon raced into a 4-1 lead in the opening set.
The British pair tried to fight back, but they went on to lose the first set 6-3 as the Japanese duo took control and then went on to win the second-round match.
Nishikori and McLachlan could now face No1 seeds Nikola Mektic and Mate Pavic in the next round, or a match with Lorenzo Musetti and Lorenzo Sonego may be on the cards too.
Team GB, meanwhile, could still have success in the doubles courtesy of Andy Murray and Joe Salisbury. Murray withdrew from the singles tournament to focus on the doubles.