title: Preclinical disposition (in vitro) of novel μ-opioid receptor selective antagonists.
abstract: 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 = P(app, B-A)/P(app, A-B), where P(app) 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 K(m) and V(max) 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.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, 410 N. 12th St., Richmond, VA 23298-0533, USA.
authors.forename: Pallabi
authors.initials: P
authors.lastname: Mitra
authors.forename: Jürgen
authors.initials: J
authors.lastname: Venitz
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yuan
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Gerk
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000042:Absorption; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D050216:Metabolic Detoxication, Phase I; D008862:Microsomes, Liver / Q000378:metabolism; D009019:Morphinans / Q000493:pharmacokinetics*; D009271:Naltrexone / Q000031:analogs & derivatives; D009292:Narcotic Antagonists / Q000493:pharmacokinetics*; D011485:Protein Binding / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C550365:17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-((3'-isoquinolyl)acetamido)morphinan; C550364:17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-((4'-pyridyl)acetamido)morphinan; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020719:Glucuronides; D009019:Morphinans; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009271:Naltrexone