Metabolism of novel anti-HIV agent 3-cyanomethyl-4-methyl-DCK by human liver microsomes and recombinant CYP enzymes

Zhuang, Xiaomei; Deng, Jing-ting; Li, Hua; Kong, Wei-li; Ruan, Jin-Xiu; Xie, Lei

doi:10.1038/aps.2011.91

Cited by 9 publications

(11 citation statements)

References 23 publications

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“…The amount of parent drug was analyzed by LC-MS/MS and the percent of remaining parent drug was calculated and compared. In vitro permeabilities of PQ-69 and DPCPX were carried out using a Caco-2 cell line, according to previously described methods [16]. In brief, drug solution (5 μM) was placed in the donor chamber and samples were taken from the receptor chamber at 90 min.…”

Section: Measurement Of Pa2 Valuesmentioning

confidence: 99%

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

Lu¹,

Wang²,

Zhang³

et al. 2014

Purinergic Signalling

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Potent and selective adenosine A 1 receptor (A 1 AR) antagonists with favourable pharmacokinetic properties used as novel diuretics and antihypertensives are desirable. Thus, we designed and synthesized a series of novel 4-alkylamino substitution-2-arylpyrazolo[4,3-c]quinolin-3-one derivatives. The aim of the present study is to characterize the biological profiles of the optimized compound, PQ-69. In vitro binding assay revealed a K i value of 0.96 nM for PQ-69 in cloned hA 1 receptor, which was 217-fold more selective compared with hA 2A receptors and >1,000-fold selectivity for hA 1 over hA 3 receptor. The results obtained from [ 35 S]-GTPγS binding and cAMP concentration assays indicated that PQ-69 might be an A 1 AR antagonist with inverse agonist activity. In addition, PQ-69 displayed highly inhibitory activities on isolated guinea pig contraction (pA2 value of 8.99) induced by an A 1 AR agonist, 2-chloro-N6-cyclopentyl adenosine. Systemic administration of PQ-69 (0.03, 0.3, 3 mg/kg) increased urine flow and sodium excretion in normal rats. Furthermore, PQ-69 displayed better metabolic stability in vitro and longer terminal elimination half-life (t 1/2 ) in vivo compared with 1,3-dipropyl-8-cyclopentylxanthine. These findings suggest that PQ-69 exhibits potent antagonist effects on A 1 AR in vitro, ex vivo and in vivo, it might be a useful research tool for investigating A 1 AR function, and it could be developed as a potential therapeutic agent.

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Section: Measurement Of Pa2 Valuesmentioning

confidence: 99%

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

Lu¹,

Wang²,

Zhang³

et al. 2014

Purinergic Signalling

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“…Consequently, it is not surprising to note that KDs feature low metabolic stability and low bioavailablity in most cases. Not only the enzymes in liver and gut, but also the carboxylesterases in rat plasma were reported to possess the catalytic abilities for KDs [7,9,10,40,50,54,56,57,58]; however, the gut bacteria-catalyzed metabolism hasn′t been reported for this kind of coumarins [54]. Taking l PA ( 3 ) for instance, its prototype is undetectable even following intravenous administration, let alone oral treatment, while most portion of d PA ( 2 ) can be quickly metabolized into l CK ( 14 ) and some other metabolites owing to the extensive distribution of isozymes in both intestine and liver tissues.…”

Section: Metabolism Of Khellactone Derivativesmentioning

confidence: 99%

“…Tandem mass spectrometric platforms, including ion trap, hybrid triple quadrupole-linear ion trap and time-of-flight mass spectrometry have been demonstrated as the reliable tools to plausibly identify the metabolites in vitro and in vivo . The fragmentation patterns of KDs have been previously proposed by various mass spectroscopic techniques [6,58]: initially, neutral loss takes place at the C-4′ position to afford a stable intermediate residue; the intermediate ion will subsequently cleave another neutral molecule from the C-3′ position to produce a diagnostic fragment ion at m / z 227 or remove an acyl group to yield the other characteristic signal at m / z 245. The cracking rules proposed for KDs are illustrated in Figure 2.…”

Section: Metabolism Of Khellactone Derivativesmentioning

confidence: 99%

“…On the basis of this rule, Ruan et al [57] suggested that PA underwent oxidation at the skeleton of coumarin. However, the oxidation site was finally placed on the side chains at C-3′ and C-4′ by our group and some other groups using the well proposed mass fragmentation patterns of KDs [9,54,58,59,61]. Step-wise oxidation was reported for KDs, from methyl group, to hydroxymethyl, then to aldehyde group, and even to carboxy group at last, such as the oxidation pathways of PA ( 1 ) [54] and CMDCK ( 10 ) [54,58].…”

Section: Metabolism Of Khellactone Derivativesmentioning

confidence: 99%

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Pharmacokinetic and Metabolic Characteristics of Herb-Derived Khellactone Derivatives, A Class of Anti-HIV and Anti-Hypertensive: A Review

Jing

Liu

et al. 2016

Molecules

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A vast number of structural modifications have been performed for khellactone derivatives (KDs) that have been widely concerned owing to their diverse biological properties, including anti-hypertension, anti-HIV, reversing P-glycoprotein (P-gp) mediated multidrug resistance, and anti-inflammation effects, to find the most active entity. However, extensive metabolism of KDs results in poor oral bioavailability, thus hindering the clinical trial performance of those components. The primary metabolic pathways have been revealed as hydrolysis, oxidation, acyl migration, and glucuronidation, while carboxylesterases and cytochrome P450 3A (CPY3A), as well as UDP-glucuronosyltransferases (UGTs) primarily mediate these metabolic pathways. Attention was mainly paid to the pharmacological features, therapeutic mechanisms and structure-activity relationships of KDs in previous reviews, whereas their pharmacokinetic and metabolic characteristics have seldom been discussed. In the present review, KDs' metabolism and their pharmacokinetic properties are summarized. In addition, the structure-metabolism relationships of KDs and the potential drug-drug interactions (DDIs) induced by KDs were also extensively discussed. The polarity, the acyl groups substituted at C-3' and C-4' positions, the configuration of C-3' and C-4', and the moieties substituted at C-3 and C-4 positions play the determinant roles for the metabolic profiles of KDs. Contributions from CYP3A4, UGT1A1, P-gp, and multidrug resistance-associated protein 2 have been disclosed to be primary for the potential DDIs. The review is expected to provide meaningful information and helpful guidelines for the further development of KDs.

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“…In vitro study indicated that CMDCK was a CYP3A4 substrate and could be metabolically eliminated rapidly in liver and intestinal microsomes. Known CYP3A4 inhibitors, such as ritonavir and ketoconazole, had significant inhibitory effects on its liver and intestinal metabolism [14]. Low solubility and extensive metabolism of CMDCK limited its oral bioavailability.…”

Section: Pharmacokinetic Studymentioning

confidence: 99%

An LC–MS–MS Method for Quantification of CMDCK: A Novel Anti-HIV Agent in Rat Plasma and Its Application to a Pharmacokinetic Study

Kong¹,

Zhuang²,

Li³

et al. 2011

Chromatographia

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A simple and sensitive LC-MS-MS method was developed and validated to quantify CMDCK, a novel non-nucleoside reverse transcriptase inhibitor in rat plasma. A simple protein precipitation with acetonitrile was used to pretreat plasma samples. Chromatographic separation was carried out on a Hypersil GOLD-C 18 (50 mm 9 2.1 mm, 5 lm) column with the mobile phase consisting of acetonitrile and 0.1% formic acid solution (60:40 v/v) at a flow rate of 0.2 mL min -1 . A triplequadrupole tandem mass spectrometer with ESI source was operated in the positive ion mode. Quantitative analysis was conducted in the selected reaction monitoring mode with precursor/product ion transitions of m/z 698/500 and 693/495, respectively for CMDCK and IS. The calibration curves were linear over the concentration range of 5-2,000 ng mL -1 with the lower limit of quantification of 5 ng mL -1 . The intra-and inter-day precisions and accuracies were satisfactory, with the coefficient of variation and the relative error being less than 13.2 and 3.38%, respectively. The recovery of CMDCK in plasma ranged from 84.6 ± 6.5 to 100.8 ± 9.3%. This LC-MS-MS method was successfully used as a new approach for the preclinical pharmacokinetics study of CMDCK in rat.

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Metabolism of novel anti-HIV agent 3-cyanomethyl-4-methyl-DCK by human liver microsomes and recombinant CYP enzymes

Cited by 9 publications

References 23 publications

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

Pharmacokinetic and Metabolic Characteristics of Herb-Derived Khellactone Derivatives, A Class of Anti-HIV and Anti-Hypertensive: A Review

An LC–MS–MS Method for Quantification of CMDCK: A Novel Anti-HIV Agent in Rat Plasma and Its Application to a Pharmacokinetic Study

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