49625-89-0Relevant academic research and scientific papers
In vitro metabolism and identification of human enzymes involved in the metabolism of methylnaltrexone
Tong, Zeen,Chandrasekaran, Appavu,Li, Hongshan,Rotshteyn, Yakov,Erve, John C. L.,DeMaio, William,Talaat, Rasmy,Hultin, Theresa,Scatina, JoAnn
, p. 801 - 807 (2010)
Methylnaltrexone (MNTX) is a peripherally acting μ-opioid receptor antagonist and is currently indicated for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Sulfation to MNTX-3-sulfate (M2) and carbonyl reduction to methyl-6α-naltrexol (M4) and methyl-6β-naltrexol (M5) are the primary metabolic pathways for MNTX in humans. The objectives of this study were to investigate MNTX in vitro metabolism in human and nonclinical species and to identify the human enzymes involved in MNTX metabolism. Of the five commercially available sulfotransferases investigated, only SULT2A1 and SULT1E1 catalyzed M2 formation. Formation of M4 and M5 was catalyzed by NADPH-dependent hepatic cytosolic enzymes, which were identified using selective chemical inhibitors (10 and 100 μM) for aldo-keto reductase (AKR) isoforms, short-chain dehydrogenase/ reductase including carbonyl reductase, alcohol dehydrogenase, and quinone oxidoreductase. The results were then compared with the effects of the same inhibitors on 6β-naltrexol formation from naltrexone, a structural analog of MNTX, which is catalyzed mainly by AKR1C4. The AKR1C inhibitor phenolphthalein inhibited MNTX and naltrexone reduction up to 98%. 5β-Cholanic acid 3α,7α-diol, the AKR1C2 inhibitor, and medroxyprogesterone acetate, an inhibitor of AKR1C1, AKR1C2, and AKR1C4, inhibited MNTX reduction up to 67%. Other inhibitors were less potent. In conclusion, the carbonyl reduction of MNTX to M4 and M5 in hepatic cytosol was consistent with previous in vivo observations. AKR1C4 appeared to play a major role in the carbonyl reduction of MNTX, although multiple enzymes in the AKR1C subfamily may be involved. Human SULT2A1 and SULT1E1 were involved in MNTX sulfation. Copyright
The Impact of Age and Genetics on Naltrexone Biotransformation
Leeder, J. Steven,Nolte, Whitney,Pearce, Robin E.,Staggs, Vincent S.,Stancil, Stephani L.
, p. 168 - 173 (2022/02/25)
Naltrexone, an opioid antagonist primarily metabolized by aldo-keto reductase 1C4 (AKR1C4), treats pediatric conditions involving compulsiveness (e.g., autism spectrum, Prader-Willi, eating disorders, non-suicidal self-injury). Pharmacokinetic variability is apparent in adults, yet no data are available for children. This study aimed to examine the impact of age and genetic variation on naltrexone biotransformation. Human liver cytosol (HLC) samples (n 5 158) isolated from children and adult organ donors were incubated with therapeutically relevant concentrations of naltrexone (0.1, 1 mM). Naltrexone biotransformation was determined by ultra-performance mass spectrometry quantification of the primary metabolite, 6-beta-naltrexol (6bN), and 6bN formation rates (pmol/mg protein/min) were calculated. HLCs from organ donors, age range 0-79 y (mean 16.0 ± 18.2 y), 37% (n 5 60) female, 20% (n 5 33) heterozygous and 1.2% (n 5 2) homozygous for co-occurring AKR1C4 variants (S145C/L311V) showed >200-fold range in 6bN formation (0.37-76.5 pmol/mg protein/min). Source of donor samples was found to be a substantial contributor to variability. Model estimates for a trimmed data set of source-adjusted pediatric samples (aged 0-18 y) suggested that AKR1C4 genetic variation, age, and sex explained 36% of the variability in 6bN formation. Although activity increased steadily from birth and peaked in middle childhood (2-5 years), genetic variation (S145C/L311V) demonstrated a greater effect on activity than did age. Naltrexone biotransformation is highly variable in pediatric and adult livers and can be partly accounted for by individual factors feasible to obtain (e.g., genetic variability, age, sex). These data may inform a precision therapeutics approach (e.g., exposure optimization) to further study Naltrexone responsiveness in children and adults.
Compounds including Cox inhibitor moiety and enhanced delivery of active drugs using same
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Page/Page column 31; 32; 33, (2017/05/06)
The presently-disclosed subject matter includes compounds including a cyclooxygenase enzyme inhibitor moiety and a moiety derived from a drug of interest. In some embodiments, the drug of interest is an opioid. In some embodiments, the compound includes a diclofenac moiety and a naltrexone or naltrexol moiety. The compounds allow for enhanced delivery rates across skin.
Synthesis and in vitro stability of amino acid prodrugs of 6-β-naltrexol for microneedle-enhanced transdermal delivery
Eldridge, Joshua A.,Milewski, Mikolaj,Stinchcomb, Audra L.,Crooks, Peter A.
, p. 5212 - 5215 (2014/12/11)
A small library of amino acid ester prodrugs of 6-β-naltrexol (NTXOL, 1) was prepared in order to investigate the candidacy of these prodrugs for microneedle-enhanced transdermal delivery. Six amino acid ester prodrugs were synthesized (6a-f). 6b, 6d, and 6e were stable enough at skin pH (pH 5.0) to move forward to studies in 50% human plasma. The lead compound (6e) exhibited the most rapid bioconversion to NTXOL in human plasma (t1/2 = 2.2 ± 0.1 h).
N-OXIDES OF 4,5-EPOXY-MORPHINANIUM ANALOGS
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Page/Page column 103-104, (2009/06/27)
Novel N-oxides of 4,5-epoxy-morphinanIum analogs are disclosed. Pharmaceutical compositions containing the N-oxides of 4,5-epoxy-morphinanium analogs and methods of their pharmaceutical uses are also disclosed. The compounds disclosed are useful, inter alia, as modulators of opioid receptors.
Process for the Preparation of 6-Beta Hydroxy Morphinan Compounds
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Page/Page column 8, (2009/12/27)
The invention provides processes for the conversion of a 6-keto morphinan to a 6-hydroxy morphinan. In particular, the invention provides a stereoselective process for the conversion of a 6-keto morphinan to a 6-beta-hydroxy morphinan.
Enhancing transdermal delivery of opiod antagonists and agonistis using codrugs links to bupropion or hydroxybupropion
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Page/Page column sheet 4; 6, (2009/01/24)
The present invention is directed to novel codrugs comprising bupropion or hydroxybupropion and an opioid antagonist or an opioid agonist joined together by chemical bonding. The codrugs provide a significant increase in the transdermal flux across human skin, as compared to the basic opioid antagonist or opioid agonist.
N-OXIDES OF 4,5-EPOXY-MORPHINANIUM ANALOGS
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Page/Page column 101-102, (2008/12/06)
Novel N-oxides of 4,5-epoxy-morphinanium analogs are disclosed. Pharmaceutical compositions containing the N-oxides of 4,5-epoxy-morphinanium analogs and methods of their pharmaceutical uses are also disclosed. The compounds disclosed are useful, inter alia, as modulators of opioid receptors.
Transdermal delivery of naltrexone hydrochloride, naltrexol hydrochloride, and bis(hydroxy-methyl)propionyl-3-0 ester naltrexone using microneedles
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Page/Page column 5; 6, (2008/06/13)
The present invention provides methods for transdermal delivery of a therapeutically effective amount of Naltrexone Hydrochloride, Naltrexol Hydrochloride, and/or Naltrexone Diol Ester using microneedles. The invention also provides methods for treatment of narcotic dependence, alcohol abuse, and/or alcoholism. Preferably, the Naltrexone Hydrochloride, Naltrexol Hydrochloride, and/or Naltrexone Diol Ester is administered by creating a microneedle-treated site in the skin of a subject by inserting microneedles, followed by applying the Naltrexone Hydrochloride, Naltrexol Hydrochloride, and/or Naltrexone Diol Ester to the microneedle-treated site.
Synthesis and hydrolytic behavior of two novel tripartate codrugs of naltrexone and 6β-naltrexol with hydroxybupropion as potential alcohol abuse and smoking cessation agents
Hamad, Mohamed O.,Kiptoo, Paul K.,Stinchcomb, Audra L.,Crooks, Peter A.
, p. 7051 - 7061 (2007/10/03)
A codrug approach for simultaneous treatment of alcohol abuse and tobacco dependence is considered as very desirable because of substantial evidence that smoking is increased significantly during drinking, and that smoking is regarded as a behavioral 'cue' for the urge to consume alcohol. The purpose of this study was to design and synthesize codrugs for simultaneous treatment of alcohol abuse and tobacco dependence. Two novel tripartate codrugs of naltrexone (NTX) and naltrexol (NTXOL) covalently linked to hydroxybupropion (BUPOH) were synthesized (25 and 26, respectively), and their hydrolytic cleavage to the parent drugs was determined. These codrugs were generally less crystalline when compared to NTX, or NTXOL, as indicated by their lower melting points, and were expected to be more lipid-soluble. Also, the calculated c logP values were found to be higher for the codrugs compared to those for NTX and NTXOL. The studies on the hydrolysis of the codrugs provided good evidence that they could be efficiently converted to the parent drugs in buffer at physiological pH. Thus, these codrugs are likely to be cleaved enzymatically in vivo to generate the parent drugs, and are considered to be potential candidates for simultaneous treatment of alcohol abuse and tobacco dependence.
