PT - JOURNAL ARTICLE AU - Pallabi Mitra AU - Jürgen Venitz AU - Yunyun Yuan AU - Yan Zhang AU - Phillip M. Gerk TI - Preclinical Disposition (In Vitro) of Novel μ-Opioid Receptor Selective Antagonists AID - 10.1124/dmd.111.038588 DP - 2011 Sep 01 TA - Drug Metabolism and Disposition PG - 1589--1596 VI - 39 IP - 9 4099 - http://dmd.aspetjournals.org/content/39/9/1589.short 4100 - http://dmd.aspetjournals.org/content/39/9/1589.full SO - Drug Metab Dispos2011 Sep 01; 39 AB - Recently, two novel N-heterocyclic derivatives of naltrexone [designated 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)acetamido]morphinan (NAP) and 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3′-isoquinolyl) acetamido]morphinan (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, where Papp is the apparent permeability, A is apical, and B is basolateral). 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 high-performance liquid chromatography-UV at 270 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-glycoprotein (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 ± 5.5 μM and 192 ± 24 pmol/min for NAQ and 1.8 ± 1.5 μM and 8.1 ± 1.4 pmol/min for NAP. Intrinsic hepatic clearance was estimated to be 13 and 5 ml · min−1 · kg−1 for NAQ and NAP, respectively. Neither NAQ nor NAP underwent detectable glucuronidation. Thus, NAP was a P-gp substrate with low apparent permeability, whereas NAQ was not a P-gp 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.