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Lowe was drawn to the role because of his personal love of politics, and his longstanding personal relationship with Martin Sheen, who was cast as President Bartlet.
When the show premiered, Seaborn was considered the lead, and the pilot centered on the character.
In 2004 Lowe starred in the TNT remake of the Stephen King miniseries Salem's Lot which was the highest rated cable program of that summer and the highest ratings TNT original programming had at the time.
In 2005 Lowe starred in the miniseries Beach Girls on the Lifetime network, based on the Luanne Rice novel of the same name.
Lowe is currently teaming up with 44 Blue to produce a reality series entitled Potomac Fever about young adults living in Washington, D. In 2011, Lowe guest starred in a recurring role on Showtime's comedy Californication.
Lowe featured as the troubled but in-demand actor Eddie Nero – a character based upon "about ten people", according to Lowe During his promotional tour for Stories I Only Tell My Friends, Lowe told Australian radio show The Kyle & Jackie O Show that during his five-day press visit to Australia in 1990, he was so badly affected by the overuse of painkillers that the only two things he remembers from the trip were being at the Sydney Zoo and getting a tattoo, although he states in his book that he does not remember getting the tattoo.
In 2014, Lowe wrote a second book titled Love Life, which was released in April that year.
He uses stories and observations from his life in a poignant and humorous series of true tales about men and women, art and commerce, fathers and sons, addiction and recovery, and sex and love.
After leaving the show, Lowe was the star and executive producer of a failed NBC drama, The Lyon's Den (2003). Although Lowe had expressed unhappiness about his decreased role on that show at the time of his departure, he has now repeatedly said that any animosity between them is over and that he was pleased to be working once more with Sorkin, whose talents as a writer Lowe highly regards. Derek Shepherd of Grey's Anatomy, which eventually went to Patrick Dempsey.
Unhappy with the stories and his lack of screen time in the fourth season, Lowe announced he would leave.
In an episode broadcast on May 16, 2010, his character was part of a multi-vehicle crash involving a large truck and was put into a coma, the storyline was wrapped up in the first episode of the fifth season; Lowe did not appear in the episode.
Eventually, Lowe left the series, not long before Sorkin and director/executive producer Thomas Schlamme unceremoniously quit over a dispute with NBC.
During the final season of The West Wing, Lowe returned to his role of Sam Seaborn, appearing in two of the final four episodes.