- In vitro metabolism and identification of human enzymes involved in the metabolism of methylnaltrexone
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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
- Tong, Zeen,Chandrasekaran, Appavu,Li, Hongshan,Rotshteyn, Yakov,Erve, John C. L.,DeMaio, William,Talaat, Rasmy,Hultin, Theresa,Scatina, JoAnn
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- The Impact of Age and Genetics on Naltrexone Biotransformation
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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.
- Leeder, J. Steven,Nolte, Whitney,Pearce, Robin E.,Staggs, Vincent S.,Stancil, Stephani L.
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p. 168 - 173
(2022/02/25)
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- Compounds including Cox inhibitor moiety and enhanced delivery of active drugs using same
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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.
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Page/Page column 31; 32; 33
(2017/05/06)
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- Synthesis and in vitro stability of amino acid prodrugs of 6-β-naltrexol for microneedle-enhanced transdermal delivery
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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).
- Eldridge, Joshua A.,Milewski, Mikolaj,Stinchcomb, Audra L.,Crooks, Peter A.
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p. 5212 - 5215
(2014/12/11)
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- N-OXIDES OF 4,5-EPOXY-MORPHINANIUM ANALOGS
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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.
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Page/Page column 103-104
(2009/06/27)
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- Process for the Preparation of 6-Beta Hydroxy Morphinan Compounds
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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.
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Page/Page column 8
(2009/12/27)
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- Enhancing transdermal delivery of opiod antagonists and agonistis using codrugs links to bupropion or hydroxybupropion
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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.
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Page/Page column sheet 4; 6
(2009/01/24)
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- N-OXIDES OF 4,5-EPOXY-MORPHINANIUM ANALOGS
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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.
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Page/Page column 101-102
(2008/12/06)
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- Transdermal delivery of naltrexone hydrochloride, naltrexol hydrochloride, and bis(hydroxy-methyl)propionyl-3-0 ester naltrexone using microneedles
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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.
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Page/Page column 5; 6
(2008/06/13)
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- Synthesis and hydrolytic behavior of two novel tripartate codrugs of naltrexone and 6β-naltrexol with hydroxybupropion as potential alcohol abuse and smoking cessation agents
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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.
- Hamad, Mohamed O.,Kiptoo, Paul K.,Stinchcomb, Audra L.,Crooks, Peter A.
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p. 7051 - 7061
(2007/10/03)
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- Reduction of drug ketones by dihydrodiol dehydrogenases, carbonyl reductase and aldehyde reductase of human liver
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In this study, we compared the enzymatic reduction of 10 drugs with a ketone group by homogeneous carbonyl reductase, aldehyde reductase and three dihydrodiol dehydrogenases of human liver cytosol. At least one and in some cases all of the three dihydrodi
- Ohara, Hirotami,Miyabe, Yoshiyuki,Deyashiki, Yoshihiro,Matsuura, Kazuya,Hara, Akira
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p. 221 - 227
(2007/10/03)
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- Stereoselective synthesis of β-naltrexol, β-nalaxol, β-naloxamine, β-naltrexamine and related compounds by the application of the Mitsunobu reaction
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As a continuation of our work, aimed at adopting the Mitsonobu reaction in the morphine series, a few representatives of dihydroisocodeines and dihydroisomorphines and their 14β-hydroxy analogues were prepared. p-Nitrobenzoic acid was used as carboxylic acid and the prepared esters were cleaved to obtain the title compounds. Using phthalimide as acidic component several new 6β-phthalimidodihydromorphine and dihydrocodeine derivatives and their 14β-hydroxy analogues have been synthesized. Cleavage of the phthalimido derivatives with hydrazine hydrate afforded the corresponding 6β-amino derivatives.
- Simon,Hostzafi,Makleit
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p. 9757 - 9768
(2007/10/02)
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- SYNTHESIS OF N-DEMETHYL-N-SUBSTITUTED 14-β-HYDROXY-ISOMORPHINE AND DIHYDROISOMORPHINE DERIVATIVES
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Some new representatives (3e-3h,5g) of a new group of structurally related morphine-agonist and antagonist compounds have been prepared in stereochemically homogeneous forms.Application of the Mitsunobu-reaction for suitable codeine derivatives (1a-1d) ga
- Hosztafi, Sandor,Simon, Csaba,Makleit, Sandor
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p. 1509 - 1520
(2007/10/02)
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- Probes for Narcotic Receptor Mediated Phenomena. 18. Epimeric 6α- and 6β-Iodo-3,14-dihydroxy-17-(cyclopropylmethyl)-4,5α-epoxymorphinans as Potential Ligands for Opioid Receptor Single Photon Emission Computed Tomography: Synthesis, Evaluation, and Radiochemistry of...
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The epimeric 6β- and 6α-iodo-3,14-dihydroxy-17-(cyclopropylmethyl)-4,5α-epoxymorphinans (1, ioxy) and (2, epioxy), respectively, were each synthesized in five steps starting with naltrexone.The configuration of the 6-iodo group of 1 was unequivocally determined to be β-based on single crystal X-ray analysis of its precursor 3-acetoxy-6β-iodo-14-hydroxy-17-(cyclopropylmethyl)-4,5α-epoxymorphinan (10).Both 1 and 2 as well as their corresponding 3-O-acetates 10 and 11 were found to readily cross the blood-brain barrier and completely reverse the analgesic effects of a 10 mg/kg intraperitoneal dose of morphine sulfate as determined by the paw withdrawal latency test.Compounds 1 and 2 were found to bind with high affinity to μ, δ and κ receptors in vitro.In general, 1 and 2 exhibited higher affinity for μ and κ receptors than naltrexone while the 6β-iodo epimer 1 (ioxy) was more potent than its epimer 2.In a comparison of the 6β-halogen substituent on binding affinity across opioid receptor subtypes, it was generally found that I>Br>F.On the basis of the results of in vitro and in vivo testing, 1 was selected as a target for radioiodination and evaluation as a potential single photon emission computed tomography imaging agent for opioid receptors.Carrier-free -1 was synthesized in near quantitative yield by the sequence of reaction of excess 3-acetoxy-6α-oxy>-14-hydroxy-17-(cyclopropylmethyl)-4,5α-epoxymorphinan (8) with anhydrous Na125I in dry acetonitrile for 90 min at 76 deg C followed by deacetylation of the product with 1:1 aqueous ammonia/acetonitrile at 25 deg C.The potential of -1 as an in vivo imaging agent for opioid receptors is evaluated and discussed.
- Costa, Brian R. de,Iadarola, Michael J.,Rothman, Richard B.,Berman, Karen F.,George, Clifford,et al.
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p. 2826 - 2835
(2007/10/02)
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- Process for the stereoselective reduction of 6- and 8-keto morphine and morphinan derivatives with formamidinesulfinic acid and compounds obtained thereby
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Process for the stereoselective synthesis of 6β-and 8β- hydroxy epimers by the chemical reduction of 6- and 8-keto derivatives in the morphine and morphinan series utilizing alkaline formamidinesulficic acid. The 6β- and 8β-hydroxy derivatives obtained according to the invention evidence narcotic antagonist and/or agonist activity and are also useful in the chemical and pharmacological standardization of various morphine and codeine derivatives and metabolites.
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