Characterization of the cellular transport mechanisms for the anti-cachexia candidate compound TCMCB07.

摘要: BACKGROUND Cachexia is a debilitating, life-threatening condition whose pathology includes reduced food intake accompanied by hypermetabolism, leading to catabolic state. The hypothalamic melanocortin system critical regulator of metabolic rate with effects being mediated through the melanocortin-4 receptor (MC4R). MC4R activation also initiation and maintenance cachexia. A major problem in design anti-cachexia drugs has been need cross blood-brain barrier access rate-controlling centres hypothalamus. overwhelming majority are only effective when administered intracerebroventricularly. TCMCB07 cyclic nonapeptide peptide antagonist parenteral activity both small large animal models. This suggests it can barrier. aim this study was examine potential transport mechanisms furthering its preclinical development for subsequent studies humans. METHODS In vitro were performed transporter-transfected cells whether or not an inhibitor as well substrate OATP1A2, OATP1B1, OATP1B3, OATP2B1, OCT2, OAT1, OAT3, MATE1, MATE2-K, P-gp (MDR1), BCRP. vivo mass balance mice evaluate absorption disposition after oral intravenous bolus administrations. RESULTS inhibited uptake prototypical substrates transfected OATP1A2 (IC50 24.0 μM), OATP1B1 6.8 μM), OATP1B3 307 μM), OATP2B1 524 μM), OCT2 1,169 μM), MATE1 8.7 μM), MATE2-K 20.7 μM) but OAT1 OAT3. did affect (MDR1)-mediated BCRP-mediated permeability cells. Importantly, direct evidence shown OATP1A2-transfected (i.e. Vmax 236 pmol/mg, Km 58.4 μM, Kd 0.39 μL/mg), demonstrating that transporter. Mass demonstrated 24.2% absorbed orally (P = 0.0033) excreted primarily bile CONCLUSIONS transporter responsible intestine pharmacologic response brain.