The antidiabetes drug, bromocriptine-QR is formulated to produce a brief pulse of dopaminergic (D) activity within the brain when taken orally within 2 hours of waking in an effort to mimic/re-establish the natural circadian peak of brain D activity observed in insulin (I) sensitive states. However, oral B is subject to extensive first pass metabolite (M) generation (> 20 Ms) that can enter the circulation and influence catecholamine receptors. Also, B or B-M interactions with the gut can potentially influence (via afferents) brain metabolism centers. As such, gut/liver influences on B may limit the full antidiabetes impact of plasma B entering the brain to briefly activate dopamine receptors shortly after its oral dosing. To test this postulate, separate groups of I resistant, glucose (G) intolerant hamsters were dosed B daily at waking for 2 weeks either intraperitoneally (ip) at its established EDmax (4 mg/kg BW) or orally (16-28 mg/kg BW) (N=6/gr) so as to produce an equivalent plasma Cmax (20 ng/ml) and bioavailability (AUC180- 2000 ng*min/ml) of B and then subjected to an ip glucose tolerance test (GTT) along with controls (N=6). Relative to control, oral B did not alter fasting plasma G (FPG), FPI, GTT G or I, or I sensitivity (HOMA-IR or Matsuda Index) however, ip B did reduce FPG, FPI, GTT G and I by 40% (P<0.02), 59% (P<0.003), 45% (P<0.002), and 54% (P<0.03) respectively and improve HOMA-IR and Matsuda Index by 76 and 264%; P<0.008 (and by an additional 73% and 577% respectively,[P<0.002]) relative to oral B) even though each administration routine produced the same plasma Cmax and bioavailability of B. The ip B also reduced body fat by 29% (P<0.006) without altering food intake, whereas oral B was without effect. These findings support the postulate that eliminating first pass B exposure to the gut can markedly enhance the antidiabetes efficacy of B and may offer a simple means of doing so for bromocriptine-QR in humans.


M. Ezrokhi: Employee; Self; VeroScience LLC. S. Luo: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at