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Jae C. Hong, Associated Press
Los Angeles Angels starting pitcher Jason Vargas throws against the Kansas City Royals during the first inning of a baseball game in Anaheim, Calif., Tuesday, May 14, 2013.

ANAHEIM, Calif. — Albert Pujols, Howie Kendrick, Josh Hamilton and Mike Trout all homered off Jeremy Guthrie, and the Los Angeles Angels handed the right-hander his first loss in 19 starts with a 6-2 victory over the Kansas City Royals on Tuesday night.

Hamilton, the Angels' right fielder, made his fourth start at designated hitter after being removed from Monday night's series-opening 11-4 loss in the seventh inning because of lightheadedness.

The 2010 AL MVP, who batted .212 with 11 RBIs in his first 38 games with the Angels after signing a five-year, $125 million contract in December, drove Guthrie's first pitch to him in the sixth inning far beyond the trees in center field with two outs to increase the lead to 4-2.

Trout ended the scoring in the seventh with his seventh homer, a towering drive over the double-decker bullpen in left field. It was the first time in Guthrie's 10-year career that he allowed four homers in a game.

Jason Vargas (2-3) gave up five hits in seven-plus innings and struck out seven. Both runs against the left-hander were knocked in by the suddenly hot Billy Butler, who had an RBI double in the fourth and a homer in the sixth.

Guthrie (5-1) yielded five runs and 11 hits over seven innings. He held the franchise record for consecutive starts without a loss while winning his previous 10 decisions. It was his first loss since Aug. 3 last year, when the Texas Rangers beat him 5-3 at Kansas City.

Butler opened the scoring with an RBI double. But the Angels responded with two runs in the bottom half, as Pujols launched his sixth homer over both bullpens leading off the inning and Kendrick hit his sixth of the season with two outs.

Trout made it 3-1 in the fifth with a sacrifice fly after the Angels put runners at the corners on singles by J.B. Shuck and Erick Aybar, who returned to the lineup after missing four games because of tightness in his right hamstring.

Los Angeles got two runners thrown out at third base by catcher Salvador Perez in the third.

Chris Iannetta drew a leadoff walk and Shuck followed with a bunt single up the third base line, but Iannetta tried to advance two bases on the play and Mike Moustakas got back to the bag in time to take Perez's throw. Shuck stopped at second on Aybar's single — but when he tried to advance on a pitch that got away from Perez about 6 feet to the right of the plate, he too was erased.

Guthrie sawed off two bats in the first inning and got more trouble than he bargained for. Trout walked with one out, then took off for second as second baseman Miguel Tejada raced in to grab Pujols' broken-bat popup.

Trout should have easily been doubled off first base, but Guthrie inexplicably ran right past the bag toward the dugout and Tejada had no one to toss the ball to as Trout scrambled back safely. Mark Trumbo followed with a broken-bat dribbler in front of the plate and was thrown out by Perez — but not before Guthrie was struck by the flying debris on his follow-through.

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NOTES: The Angels are 4-0 when Hamilton is the DH. He is 8 for 25 against Guthrie with three home runs. ... The last pitcher to give up four homers against the Angels in a game was Oakland's Dan Straily, on Aug. 8, 2012, in his second big league start (Kendrys Morales two, Iannetta and Torii Hunter). ... Kansas City has gotten only one other home run from the cleanup spot through the first 36 games — by Butler on Saturday against the Yankees — and five from the leadoff spot. All of those were by Alex Gordon, who was shifted to the No. 3 hole six games ago and has gone deep once since then. ... Angels LHP C.J. Wilson will match up against LHP Chris Sale of the White Sox for the second time in six days on Friday night in the second game of their four-game series. Sale outpitched Wilson with a one-hitter on Sunday at Chicago, beating the Angels 3-0.