The Sweden international is understood to want a move to Liverpool, with the Merseyside club reportedly having the funds to complete the transfer.
Newcastle, however, are reluctant to sanction any deal without first securing a suitable replacement. That search has proven problematic, with the Magpies struggling to identify a player of comparable quality to the 24-year-old.
Howe acknowledged that the club's stance could be tested, even if a replacement is not found, given Isak's desire to leave.
The forward is currently training away from the main squad and is not expected to feature in Newcastle's Premier League opener against Aston Villa on 16 August. His absence will likely be felt, with Isak having been a key figure in Newcastle's attack since joining from Real Sociedad in 2022.
Before the league campaign begins, the Magpies will face Atletico Madrid in a friendly on Sunday, a fixture that could further underline their attacking options - or lack thereof - should Isak's departure move closer.
Liverpool are believed to be monitoring the situation closely, with the Anfield hierarchy keen to strengthen their forward line ahead of the new season.
Asked if the club can tell Isak to stay, Howe said: "It's not that straightforward, otherwise we would have done that a long time ago.
"I don't think we're in a position to be able to do that currently."
After the 2-2 draw with Espanyol, Howe added: "I'd want Alex to be playing today, I'd want him training tomorrow.
"We would love the player to be with us - let me make that absolutely clear. There's no part of me that doesn't want that outcome.
"But I don't see that changing before Aston Villa, the current situation we're in."
Liverpool are eyeing PSG's Bradley Barcola as a fallback option if their pursuit of Newcastle's Alexander Isak fails, with transfer experts Fabrizio Romano and Florian Plettenberg confirming the Reds' interest in the 22-year-old winger.
Liverpool manager Arne Slot has played down his club's transfer link to Alexander Isak while confirming that Darwin Nunez is close to leaving the current Premier League champions.
Newcastle United are closing in on a deal to sign Brentford's prolific striker Yoane Wissa as the European summer transfer window nears its climax, with growing confidence that a breakthrough is imminent.
Newcastle United's star striker Alexander Isak remains at the heart of a gripping transfer saga, with the 25-year-old pushing for a blockbuster move to Premier League champions Liverpool.
