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 = 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.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA024022]; the National Institutes of Health National Center on Minority Health and Health Disparities [Grant MD002256]; the Thomas F. and Kate Miller Jeffress Trust; and the Virginia Commonwealth University School of Pharmacy.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.038588.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- MOR
- μ-opioid receptor
- NAP
- (17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)acetamido]morphinan)
- NAQ
- 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3′-isoquinolyl) acetamido]morphinan)
- MDCKII-MDR1
- Madin-Darby canine kidney strain II-multidrug resistance transporter 1
- HLM
- human liver microsomes
- GF120918
- N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
- P-gp
- P-glycoprotein, multidrug resistance transporter 1, gene symbol ABCB1
- HPLC
- high-performance liquid chromatography
- ACN
- acetonitrile
- A
- apical
- B
- basolateral
- PDR
- permeability directional ratio
- IVIVE
- in vitro-in vivo extrapolation
- BCRP
- breast cancer resistance protein.
- Received February 5, 2011.
- Accepted June 17, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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