Aminoindanes--the next wave of 'legal highs'?

Due to its closed ring system, 2-aminoindane is a conformationally rigid analogue of amphetamine. Internet websites offering synthetic compounds as 'research chemicals' have recently been advertising 5,6-methylenedioxy-2-aminoindane (MDAI), 5, 6-methylenedioxy-N-methyl-2-aminoindane (MDMAI), 5-iodo-2-aminoindane (5-IAI), and 5-methoxy-6-methyl-2-aminoindane (MMAI). The chemistry, pharmacology, and toxicological aspects of this new class of psychoactive substances are reviewed, as these could become the next wave of 'legal highs'.     

Further studies on metabolism in vivo of 3,4,3′,4′-tetrachlorobiphenyl in rats: Identification of minor metabolites in rat faeces

1. Metabolism in vivo of 3,4,3′,4′-tetrachlorobiphenyl (TCB) was investigated in male Wistar rats.

2. Five new minor metabolites in addition to two previously identified major metabolites (5-hydroxy-3,4,3′,4′-TCB and 4-hydroxy-3,5,3′,4′-TCB) were isolated as methylated derivatives from faeces of rats treated with 3,4,3′,4′-TCB, by silica gel column chromatography and subsequent preparative t.l.c.

3. Among these methylated metabolites, three were identified as dimethoxy-TCB, and one as monomethoxy-trichlorobiphenyl (TriCB), by g.l.c.-mass spectrometry. By comparison with synthetic standards they were fully identified as 2,5-dimethoxy-3,4,3′,4′-TCB, 4,4′-dimethoxy-3,5,3′,5′-TCB, 5,6-dimethoxy-3,4,3′,4′-TCB, and 4-methoxy-3,3′,4′-TriCB, respectively. The structures of these metabolites in rat faeces should therefore be 2,5-dihydroxy-3,4,3′,4′-TCB, 4,4′-dihydroxy-3,5,3′,5′-TCB, 5,6-dihydroxy-3,4,3′,4′-TCB, and 4-hydroxy-3,3′,4′-TriCB.

4. One further metabolite was isolated, which was shown to be an oxepin, existing in a state of equilibration with the 4′,5′-oxide of the major metabolite, 4-hydroxy-3,5,3′,4′-TCB, by mass and ¹H-n.m.r. spectra. On standing for several months, this metabolite isomerized to a new compound with a different g.l.c. retention time, which on methylation yielded a product identical with synthetic 4,4′-dimethoxy-3,5,3′,5′-TCB by g.l.c.-mass spectrometry. From these results this metabolite was assumed to be an oxepin, equilibrated with 4-hydroxy-4′,5′-epoxy-3,5,3′,4′-TCB.     

Metabolism of o-[methyl-14C]toluidine in the F344 rat

1. Following a single dose (400?mg/kg s.c.) of o-[methyl-¹⁴C]toluidine to male F344 rats, 56% of the ¹⁴C was recovered in the 24?h urine, 2–3% in the faeces and 1% as exhaled ¹⁴CO₂. After 48h, 83.9% of the ¹⁴C appeared in the urine, 3.3% in the faeces and 1.4% was exhaled.

2. Ether-extractable urinary metabolites were separated by?h.p.l.c. and identified as: o-toluidine (5.1% dose); azoxytoluene (0.2%); o-nitrosotoluene (≤0.1%); N-acetyl-o-toluidine (0.2%); N-acetyl-o-aminobenzyl alcohol (0.3%); 4-amino-m-cresol (0.6%); N-acetyl-4-amino-m-cresol (0.3%); anthranilic acid (0.3%) and N-acetylanthranilic acid (0.3%).

3. Acid-conjugated urinary metabolites (51% of dose), separated by paper electrophoresis and by Sephadex LH-20 chromatography, were identified as sulphates of 4-amino-m-cresol (27.8% dose), N-acetyl-4-amino-m-cresol (8.5%), and 2-amino-m-cresol (2.1%), and glucuronides of 4-amino-m-cresol (2.6%), N-acetyl-4-amino-m-cresol (2.1%), and N-acetyl-o-aminobenzyl alcohol. Evidence for a double acid conjugate of 4-amino-m-cresol was also found.

4. These results show that N-acetylation and hydroxylation at the 4 position of o-toluidine are major metabolic pathways in the rat. Minor pathways include hydroxylation at the 6 position, oxidation of the methyl group and oxidation of the amino group. Sulphate conjugates predominate over glucuronides by a ratio of 6:1.     

Identification of three new phase II metabolites of a designer drug methylone formed in rats by N-demethylation followed by conjugation with dicarboxylic acids

1.?Methylone (3,4-methylenedioxy-N-methylcathinone, MDMC), which appeared on the illicit drug market in 2004, is a frequently abused synthetic cathinone derivative. Known metabolic pathways of MDMC include N-demethylation to normethylone (3,4-methylenedioxycathinone, MDC), aliphatic chain hydroxylation and oxidative demethylenation followed by monomethylation and conjugation with glucuronic acid and/or sulphate.

2.?Three new phase II metabolites, amidic conjugates of MDC with succinic, glutaric and adipic acid, were identified in the urine of rats dosed subcutaneously with MDMC.HCl (20?mg/kg body weight) by LC-ESI-HRMS using synthetic reference standards to support identification.

3.?The main portion of administered MDMC was excreted unchanged. Normethylone, was a major urinary metabolite, of which a minor part was conjugated with dicarboxylic acids.

4.?Previously identified ring-opened metabolites 4-hydroxy-3-methoxymethcathinone (4-OH-3-MeO-MC), 3-hydroxy-4-methoxymeth-cathinone (3-OH-4-MeO-MC) and 3,4-dihydroxymethcathinone (3,4-di-OH-MC) mostly in conjugated form with glucuronic and/or sulphuric acids were also detected.

5.?Also, ring-opened metabolites derived from MDC, namely, 4-hydroxy-3-methoxycathinone (4-OH-3-MeO-C), 3-hydroxy-4-methoxycathinone (3-OH-4-MeO-C) and 3,4-dihydroxycathinone (3,4-di-OH-C) were identified for the first time in vivo.     

Pharmacokinetic analysis of factors determining elimination pathways for sulfate and glucuronide metabolites of xenobiotics II: Studies with isolated perfused rat liver

1.?To elucidate the determining factors for elimination pathways of sulfate and glucuronide metabolites of xenobiotics, a single-pass perfusion of 4-methylumbelliferone (4MU) or p-nitrophenol (pNP) was performed with an isolated rat liver preparation.

2.?Without bovine serum albumin in the perfusion system, clearance calculated based on the unbound concentration in the liver clearly showed that the net efflux clearances (CL_eff) of sulfates from the sinusoidal membrane were much higher than those of glucuronides and that the biliary excretion clearances (CL_b) of glucuronides were approximately two times larger than those of sulfates.

3.?The ratios of CL_eff to CL_b were much higher for sulfates than those for glucuronides. The bile-oriented elimination of glucuronides or sinusoidal efflux-oriented elimination of sulfates was observed even using the perfusate including 3% bovine serum albumin, but the sinusoidal efflux of sulfates was extensively enhanced by bovine serum albumin in the perfusate. The mechanisms behind this stimulatory effect remain to be elucidated.

4.?For both compounds, CL_b of glucuronide was comparable with CL_b of sulfate, meaning that CL_b is not responsible for the biliary excretion of glucuronides at extensively higher rate than sulfates.

5.?Higher concentration of glucuronides in the liver, partly caused by much lower CL_eff of glucuronides than that of sulfates, is likely responsible for the bile-oriented excretion of glucuronides. The extensive sinusoidal efflux of sulfates, leading to the urine-oriented excretion, is attributed to the substantially higher CL_eff than CL_b.

6.?In conclusion, the sinusoidal efflux is an important factor for determining elimination pathways of both sulfates and glucuronides, although further studies are needed to clarify the mechanisms of the sinusoidal efflux.     

Two new isoflavanones from Erythrina costaricensis

Two new isoflavanones, 5,3′-dihydroxy-4′-methoxy-5′-(3-methyl-1,3-butadienyl)-2″,2″-dimethylpyrano[5,6:6,7]isoflavanone (1) and 5,3′-dihydroxy-5′-(3-hydroxy-3-methyl-1-butenyl)-4′-methoxy-2″,2″-dimethylpyrano[5,6:6,7]isoflavanone (2), together with two known isoflavonoids, cristacarpin, and euchrenone b₁₀, were isolated from the stems of Erythrina costaricensis. Their structures were established on the basis of spectroscopic evidence. These new compounds are rare isoflavanones, possessing both a 2,2-dimethylpyran substituent and a prenyl analog. The antibacterial activities of 1 and 2 against the methicillin-resistant Staphylococcus aureus were examined.     

Metabolism and subsequent covalent binding of benzo[a]pyrene to macromolecules in gonads and liver of ripe English sole (Parophrys vetulus)

1. Ripe English sole (Parophrys vetulus) force-fed [³H]benzo[a]pyrene, contained 1% of the dose in liver, 0.2% in ovary and 0.1% in testis, after 24h. No significant change occurred in levels of radioactivity from 24 to 168h.

2. Gonads and blood contained substantially larger proportions of unchanged benzo[a]pyrene (15–37% of tissue radioactivity) and organic solvent-soluble metabolites (6–35%) than did liver and bile.

3. T.l.c. revealed the presence of phenols, quinones, 7,8-dihydro-7,8-dihydroxy- and 9,10-dihydro-9,10-dihydroxy-benzo[a]pyrene in liver and gonads.

4. A small proportion (<10%) of the radioactivity in liver and gonads was present as glucuronides and sulphates; bile contained a higher proportion (ca. 20%) of total radioactivity as glucuronides and sulphates.

5. Benzo[a]pyrene intermediates were covalently bound to liver proteins and DNA, and to a lesser extent to gonadal proteins (male and female fish) and gonadal DNA (confirmed for testis only).     

Biotransformation of 3-(2′,4′,5′-Triethoxybenzoyl)propionic Acid,a New Biliary Smooth Muscle Relaxant with Choleretic Activity,in Rats

1. By the combined use of deuterium labelling and gas chromatographic-mass spectrometric analysis, the metabolite pattern of 3-(2′,4′,5′-triethoxybenzoy!)propionic, acid (triethoxybenzoylpropionic acid), a new biliary smooth muscle relaxant with choleretic activity, has been determined in the rat.

2. The metabolites excreted in urine and/or bile were isolated and characterized as follows: the parent drug, 3-(2′,5′-diethoxy-4′-hydroxybenzoyl)propionic acid (metabolite II), 3-(2′-ethoxy-4′-hydroxy-5′-methoxybenzoyl)propionic acid or 3-(2′-ethoxy-5′-hydroxy-4′-methoxybenzoyl)propionic acid (III), 3-(2′,4′-diethoxy-5′-hydroxybenzoyl)propionic acid (V) and 3-[2′,4′-diethoxy-5′-(2-hydroxyethoxy)benzoyl]propionic acid (VI).

3. The primary route of biotransformation of triethoxybenzoylpropionic acid in the rat was either O-de-ethylation at the C-4′ and C-5′ positions or β-hydroxylation of the ethoxy group at the C-5′ position in the parent molecule.

4. All these excreted products except metabolite VI were eliminated both unconjugated and in conjugates (probably glucuronides and/or sulphates).

5. The rat excreted mainly metabolites V and VI in the urine and parent drug, metabolites V and VI in the bile.     

3,4,5-Trimethoxycinnamic Acid and Related Compounds I. Metabolism by the Rat Intestinal Microflora

1. The metabolism of some substituted cinnamic and phenylpropionic acids by mixed cultures of rat caecal micro-organisms has been investigated. The compounds studied were: 3,4,5-trimethoxy-, 4-hydroxy-3,5-dimethoxy- and 3,5-dimethoxycinnamic acid, and 3,4,5-trimethoxy-, 3-hydroxy-4,5-dimethoxy-, 4-hydroxy-3,5-dimethoxy-, 3,4-dihydroxy-5-methoxy-, 3,5-dihydroxy-4-methoxy-, 3,4,5-trihydroxy-, 3,5-dimethoxy- and 3-hydroxy-5-methoxy-phenyl-propionic acid.

2. The metabolic reactions found to occur were hydrogenation of the double bond, O-demethylation and p-dehydroxylation. No decarboxylation was detected.

3. The ultimate metabolic product was 3,5-dihydroxyphenylpropionic acid which was formed from all of the trihydric derivatives.

4. The metabolic sequence from the trimethoxy derivatives to 3,5-dihydroxyphenylpropionic acid was not found to proceed along a single pathway. However, the major pathway appears to involve an initial meta-O-demethylation followed by para-O-demethylation and, then after the ultimate O-demethylation, p-dehydroxylation.     

Pharmacological profiles of aminoindanes,piperazines, and pipradrol derivatives

Aminoindanes, piperazines, and pipradrol derivatives are novel psychoactive substances found in “Ecstasy” tablets as replacements for 3,4-methylenedioxymethamphetamine (MDMA) or substances sold as “ivory wave.” The pharmacology of these MDMA- and methylphenidate-like substances is poorly known. We characterized the pharmacology of the aminoindanes 5,6-methylenedioxy-2-aminoindane (MDAI), 5-iodoaminoindane (5-IAI), and 2-aminoindane (2-AI), the piperazines meta-chlorophenylpiperazine (m-CPP), trifluoromethylphenylpiperazine (TFMPP), and 1-benzylpiperazine (BZP), and the pipradrol derivatives desoxypipradrol (2-diphenylmethylpiperidine [2-DPMP]), diphenylprolinol (diphenyl-2-pyrrolidinemethanol [D2PM]), and methylphenidate. We investigated norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine [5-HT]) uptake inhibition using human embryonic kidney 293 (HEK 293) cells that express the respective human monoamine transporters (NET, DAT, and SERT). We also evaluated the drug-induced efflux of NE, DA, and 5-HT from monoamine-preloaded cells and the binding affinity to monoamine transporters and receptors, including trace amine-associated receptor 1 (TAAR₁). 5-IAI and MDAI preferentially inhibited the SERT and NET and released 5-HT. 2-AI interacted with the NET. BZP blocked the NET and released DA. m-CPP and TFMPP interacted with the SERT and serotonergic receptors. The pipradrol derivatives were potent and selective catecholamine transporter blockers without substrate releasing properties. BZP, D2PM, and 2-DPMP lacked serotonergic activity and TAAR₁ binding, in contrast to the aminoindanes and phenylpiperazines. In summary, all of the substances were monoamine transporter inhibitors, but marked differences were found in their DAT vs. SERT inhibition profiles, release properties, and receptor interactions. The pharmacological profiles of D2PM and 2-DPMP likely predict a high abuse liability.     

Stereoselective hydroxylation by CYP2C19 and oxidation by ADH4 in the in vitro metabolism of tivantinib

1.?In prior studies, it has been shown that tivantinib is extensively metabolized in humans to many oxidative metabolites and glucuronides. In order to identify the responsible enzymes, we investigated the in vitro metabolism of tivantinib and its four major circulating metabolites.

2.?The primary isoforms involved in the elimination of tivantinib were CYP2C19 and CYP3A4/5. CYP2C19 showed catalytic activity for the formation of M5 (hydroxylated metabolite), but not for M4 (a stereoisomer of M5), whereas CYP3A4/5 catalyzed the formation of both metabolites. For the elimination of M4, M5 and M8 (keto-metabolite), CYP3A4/5 was the major cytochrome P450 isoform and UGT1A9 was mainly involved in the glucuronidation of M4 and M5.

3.?ADH4 was identified as one of the major alcohol dehydrogenase isoforms contributing to the formation of M6 (sequential keto-metabolite of M4 and M5) and M8. The substrate preference of ADH for M4, and not M5, was observed in the formation of M6.

4.?In conclusion, CYP2C19, CYP3A4/5, UGT1A9 and ADH4 were the primary drug metabolizing enzymes involved in the in vitro metabolism of tivantinib and its metabolites. The stereoselective hydroxylation by CYP2C19 and substrate stereoselectivity of ADH4-catalyzed oxidation in the in vitro metabolism of tivantinib was discovered.     

The metabolism of 14C-tazadolene succinate in the dog

1. Beagle dogs dosed orally with ¹⁴C-tazadolene succinate excreted much of the dose in the urine (mean 63.1% in 5 days with most excreted in the first 24?h). A lesser proportion of the dose was excreted in the faeces (mean 20.7%) and again most of this was voided in the first 24?h.

2. Four metabolites were identified and quantified in the urine, namely 3-hydroxy-(M1), 4-hydroxy- (M2a), and 3-methoxy-4-hydroxy-tazadolene (M2b) and N-[2-(phenylmethylene)cyclohexyl]-β-alanine (M3).

3. In the 24?h urine, M2a and b glucuronides accounted for 17.7% dose, unconjugated M2a and b for 11.3%, and M3 for 18.3%. Insufficient M1 was present to be quantified. The same metabolites were seen in the 24h faeces, but at lower concn. Thus M2a and b glucuronides, M2a and b, and M3 were 3.2%, 4.9% and 3.5% dose respectively.

4. All three phenols were present in plasma as their glucuronides as well as the β-alanine derivative. They all had the same t_max of 2h and t_1/2λ1 of the order of 1?h.     

Metabolism of 3-(Hydroxymethyl)-8-methoxychromone in the Rat: II. Classification and Identification of Urinary Drug Metabolites

1. Five metabolites were isolated from the urine of dogs dosed with 3-(hydroxymethyl)-8-methoxy[4-¹⁴C]chromone. These were identified as 8-methoxychromone, 2-hydroxy-3-methoxyacetophenone, 3-(hydroxymethyl)-8-hydroxychromone, 8-hydroxychromone and 2,3-dihydroxyacetophenone.

2. These compounds were also present in the urine of rats treated with labelled drug, together with unchanged drug and two intermediate metabolites, 3-carboxy-8-methoxychromone and 3-(carboxymethyl)-8-hydroxychromone.

3. In addition to the unconjugated labelled compounds, glucuronides and sulphates were identified.

4. Quantitative data were obtained for all of the 20 labelled compounds in rat urine.

5. A scheme is presented for the biotransformation of 3-(hydroxymethyl)-8-methoxychromone in rats and dogs, and a mechanism for scission of the γ-pyrone ring is suggested.     

Identification of goat and mouse urinary metabolites of the pneumotoxin, 3-methylindole

1. Urine from goats dosed i.v. With 3-methylindole (3MI; 15?mg/kg) or [methyl-¹⁴C] 3MI (15?mg/kg, 0.5 μCi/kg) contained at least 11 metabolites of 3MI.

2. Goat metabolized 3MI to sulfate conjugates of 4- or 7-hydroxy-3-methyloxindole, 5- or 6-hydroxy-3-methyloxindole, and 3,5- or 6-dihydroxy-3-methyloxindole; glucuronic acid conjugates of indole-3-carboxylic acid and 4- or 7-hydrexy-3-methyl-oxindole; and unconjugated 3-hydroxy-3-methyloxindole. Diastereoisomeric glucuronic acid conjugates of 3-hydroxy-3-methyloxindole were also identified in goat urine.

3. Urine from mice dosed i.p. With 3MI (400mg/kg) or [ring-UL-¹⁴C] 3MI (400?mg/kg, 125 μCi/kg) contained at least six metabolites of 3MI.

4. Mice metabolized 3MI to glucuronic acid conjugates of 3,5- or 6-dihydroxy-3-methyloxindole, 5- or 6-hydroxy-3-methyloxindole, and indole-3-carboxylic acid; and unconjugated indole-3-carboxylic acid. Unconjugated 3-hydroxy-3-methyloxindole was identified in mouse urine in a previous report.

5. Both goats and mice metabolized 3MI to a mercapturate, 3-[(N-acetyl-L-cystein-S-yl)methyl]indole, which has been previously identified and was confirmed in this study.

6. 3-Methyloxindole was not identified in the urine of either goats or mice.

7. The major pathways of 3MI biotransformation in goats and mice is the formation of mono- and dihydroxy-3-methyloxindoles and their subsequent conjugation with glucuronic acid or sulfate.

8. There are no apparent qualitative differences in the biotransformation of 3MI between goats and mice that can account for their different sensitivities to 3MI induced lung injury.     

2,5-Dihydroxy-4-methoxybenzophenone: a novel major in vitro metabolite of benzophenone-3 formed by rat and human liver microsomes

1.?When benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) was incubated with liver microsomes of untreated rats in the presence of NADPH, the 5-hydroxylated metabolite, 2,5-dihydroxy-4-methoxybenzophenone (5-OH-BP-3), was formed as a major novel metabolite of BP-3. The 4-desmethylated metabolite, 2,4-dihydroxybenzophenone (2,4-diOH-BP), previously reported as the major in vivo metabolite of BP-3, was also detected. However, the amount of 5-OH-BP-3 formed in vitro was about the same as that of 2,4-diOH-BP.

2.?The oxidase activity affording 5-OH-BP-3 was inhibited by SKF 525-A and ketoconazole, and partly by quinidine and sulfaphenazole. The oxidase activity affording 2,4-diOH-BP was inhibited by SKF 525-A, ketoconazole and α-naphthoflavone, and partly by sulfaphenazole.

3.?The oxidase activity affording 5-OH-BP-3 was enhanced in liver microsomes of dexamethasone-, phenobarbital- and 3-methylcholanthrene-treated rats. The activity affording 2,4-diOH-BP was enhanced in liver microsomes of 3-methylcholanthrene- and phenobarbital-treated rats.

4.?When examined recombinant rat cytochrome P450 isoforms catalyzing the metabolism of BP-3, 5-hydroxylation was catalyzed by P450 3A2, 1A1, 2B1, 2C6 and 2D1, while 4-desmethylation was catalyzed by P450 2C6 and 1A1.     

Identification of the metabolites of episesamin in rat bile and human liver microsomes

Episesamin is an isomer of sesamin, resulting from the refining process of non-roasted sesame seed oil. Episesamin has two methylendioxyphenyl groups on exo and endo faces of the bicyclic skeleton. The side methylendioxyphenyl group was metabolized by cytochrome-P450. Seven metabolites of episesamin were found in rat bile after treatment with glucuronidase/arylsulfatase and were identified using NMR and MS. The seven metabolites were (7α,7'β,8α,8'α)-3,4-dihydroxy-3',4'-methylenedioxy-7,9':7',9-diepoxylignane (EC-1-1), (7α,7'β,8α,8'α)-3,4-methylenedioxy-3',4'-dihydroxy-7,9':7',9-diepoxylignane (EC-1-2) and (7α,7'β,8α,8'α)-3,4:3',4'-bis(dihydroxy)-7,9':7',9-diepoxylignane (EC-2), (7α,7'β,8α,8'α)-3-methoxy-4-hydroxy-3',4'-methylenedioxy-7,9':7',9-diepoxylignane (EC-1m-1), (7α,7'β,8α,8'α)-3,4-methylenedioxy-3'-methoxy-4'-hydroxy-7,9':7',9-diepoxylignane (EC-1m-2), (7α,7'β,8α,8'α)-3-methoxy-4-hydroxy-3',4'-dihydroxy-7,9':7',9-diepoxylignane (EC-2m-1) and (7α,7'β,8α,8'α)-3,4-dihydroxy-3'-methoxy-4'-hydroxy-7,9':7',9-diepoxylignane (EC-2m-2). EC-1-1, EC-1-2 and EC-2 were also identified as metabolites of episesamin in human liver microsomes. These results suggested that similar metabolic pathways of episesamin could be proposed in rats and humans.     

Preclinical metabolism and pharmacokinetics of NVS-CRF38, a potent and orally bioavailable corticotropin-releasing factor receptor 1 antagonist

Abstract

1.?The pharmacokinetic properties and metabolism of NVS-CRF38 [7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole], a novel corticotropin-releasing factor receptor 1 (CRF₁) antagonist, were determined in vitro and in animals.

2.?NVS-CRF38 undergoes near complete absorption in rats and dogs. In both species the compound has low hepatic extraction and is extensively distributed to tissues.

3.?In rat and human hepatic microsomes and cryopreserved hepatocytes from rat, dog, monkey and human, NVS-CRF38 was metabolised to form O-desmethyl NVS-CRF38 (M7) and several oxygen adducts (M1, M3, M4, M5 and M6). In hepatocytes further metabolites were observed, specifically the carboxylic acid (M2) and conjugates (sulphate and glucuronide) of M7.

4.?Formation of primary metabolites in hepatocytes was blocked by the cytochrome P450 enzyme (P450) suicide inhibitor 1-aminobenzotriazole, implicating P450 enzymes in the primary metabolism of this compound.

5.?NVS-CRF38 is weakly bound to plasma proteins from rat (fu_b?=?0.19), dog (fu_b?=?0.25), monkey (fu_b?=?0.20) and humans (fu_b?=?0.23). Blood-to-plasma partition for NVS-CRF38 approaches unity in rat and human blood.

6.?The hepatic clearance of NVS-CRF38 in humans is predicted to be low (extraction ratio?～?0.2) based on scaling from drug depletion profiles in hepatic microsomes.     

The complex degradation and metabolism of quercetin in rat hepatocyte incubations

Abstract

1.?The current study demonstrated that there is still new information to be obtained on the chemical and biological transformation of the widely studied flavonoid quercetin.

2.?In rat hepatocytes, 35 metabolites of quercetin were observed by using high-resolution mass spectrometry. The metabolites included glucuronides, sulfates, mixed sulfate/glucuronide metabolites and methylated versions of these metabolites.

3.?Several metabolites were formed from chemical degradation products of quercetin which were found to form in Krebs–Henseleit (KH) buffer, degradants of quercetin were also formed in the buffer under the conditions used for hepatocyte incubations.

4.?The degradants and metabolites of quercetin were characterized by using high-resolution MS². It was observed that the glutathione (GSH) conjugates of quercetin formed in large amounts in ammonium bicarbonate solution although the pattern of conjugates formed was different from that observed in hepatocytes suggesting some degree on enzymatic control on GSH conjugate formation in the hepatocyte incubations.

5.?GSH conjugates were not formed when GSH was included in incubations of quercetin in KH buffer alone and only small amounts of quercetin degradation occurred. Instead, GSH was extensively converted into GSSG, thus presumably reducing the levels of oxygen in the incubation thus preventing quercetin degradation.     

New anthraquinone dimer from the root bark of Cassia artemisioides (Gaudich. Ex. DC) Randell

The phytochemical investigation of the root bark of Cassia artemisioides (Gaudich. Ex. DC) Randell resulted in the isolation of one new anthraquinone 1,1′-dihydroxy-3,3′-dimethyl-8,8′-dimethoxy-6,6′-O-bianthraquinone (1) along with four known anthraquinones 1,6-dihydroxy-8-methoxy-3-methylanthraquinone (2), 1-hydroxy-8-methoxy-3-methylanthraquinone (3), 1,8-dihydroxy-6-methoxy-3-methylanthraquinone (4), and 1,6,8-trihydroxy-3-methylanthraquinone (5). The structures of the compounds were elucidated using spectroscopic techniques including 1D and 2D NMR. The compounds were evaluated for antioxidant activity. 1,6,8-Trihydroxy-3-methyl anthraquinone (5) showed good activity among the tested compounds.     

Parathesilactones and Parathesiquinones from Branches of Parathesis amplifolia.

Abstract

Three new lactone derivatives, (3E.)-5,6-dihydroxy-3-(3-hydroxy-4-nonyl-5-oxofuran-2(5H.)-ylidene)-7-nonyl-1-benzofuran-2(3H.)-one (1), (3E.)-5,6-dihydroxy-3-(3-hydroxy-4-decyl-5-oxofuran-2(5H.)-ylidene)-7-decyl-1-benzofuran-2(3H.)-one (2), and (3E.)-5,6-dihydroxy-3-(3-hydroxy-4-undecyl-5-oxofuran-2(5H.)-ylidene)-7-undecyl-1-benzofuran-2(3H.)-one (3), denominated as parathesilactones A, B, C, respectively, and two new quinone derivatives, (2,7,8-trihydroxy-3,6-didecyldibenzo[b,d.]furan-1,4-dione (4) and (2,7,8-trihydroxy-3,6-dinonyldibenzo[b,d.]furan-1,4-dione) (5), denominated as parathesiquinones A, B, respectively, were isolated from the branches of Parathesis amplifolia. Lund. (Myrsinaceae). In addition, three known triterpenes, α.-amyrin (6), β.-amyrin (7), and bauerenol (8), and four known alkenylresorcinols, 5-pentadec-8-enyl resorcinol (9), 5-pentadec-10-enyl resorcinol (10), 5-heptadec-8-enyl resorcinol (11), and 5-heptadec-10-enyl resorcinol (12), were also isolated. The structure elucidation was achieved by means of MS, GC-MS, IR, ¹H, ¹³C spectroscopy including Heteronuclear Multiple Quantum Coherence (HMQC), and Heteronuclear Multiple Bond Correlation (HMBC) techniques.