TY - JOUR T1 - Preclinical Disposition (in vitro) of Novel μ-Opioid Receptor Selective Antagonists JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.111.038588 SP - dmd.111.038588 AU - Pallabi Mitra AU - Jurgen Venitz AU - Yunyun Yuan AU - Yan Zhang AU - Phillip M Gerk Y1 - 2011/06/17 UR - http://dmd.aspetjournals.org/content/early/2011/06/17/dmd.111.038588.abstract N2 - Recently, two novel N-heterocyclic derivatives of naltrexone, (designated NAP and NAQ) have been proposed as μ opioid receptor (MOR) selective antagonists. The goal of this study was to examine their absorption and metabolism. The bidirectional transport of NAP and NAQ was determined in Caco-2 and MDCKII-MDR1 cells, and the permeability directional ratio (PDR) was estimated (PDR = Papp,B-A/Papp,A-B). Oxidative metabolism of NAQ (0.5-80 µM) and NAP (0.5-30 µM) was determined in pooled human liver microsomes. The reaction monitored the disappearance of NAQ/NAP. NAP and NAQ were quantitated by HPLC-UV at 270 nm or 232 nm, respectively. The permeability of NAQ or NAP was similar to that of naltrexone or paracellular markers, respectively. NAP also exhibited a high PDR, and was determined to be a P-gp substrate. Unbound fractions in human plasma for NAQ and NAP were 0.026±0.019 and 0.85±0.12, respectively. The metabolic oxidative reaction rates, fitted to a Michaelis-Menten model, yielded Km and Vmax values of 15.8±5.5µM, 192±24 pmol/min for NAQ; and 1.8±1.5µM, and 8.1±1.4 pmol/min for NAP. Intrinsic hepatic clearance was estimated to be 13 and 5 mL/min/kg for NAQ and NAP, respectively. Neither NAQ nor NAP underwent detectable glucuronidation. Thus, NAP was a Pgp substrate with low apparent permeability while NAQ was not a Pgp substrate and showed better permeability. Therefore, in contrast to NAP, NAQ would be more suitable for oral absorption and penetration of the blood-brain barrier, yielding potential pharmacokinetic and pharmacodynamic advantages over naltrexone. ER -