1792-P: Circumventing Gut Exposure to Bromocriptine (b) Administration Multiplies Its Antidiabetes Efficacy vs. Its Equimolar Plasma Level Derived from Oral Dosing

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 ED_max (4 mg/kg BW) or orally (16-28 mg/kg BW) (N=6/gr) so as to produce an equivalent plasma C_max (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 C_max 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.