Physicochemical Effects of the Major Quassinoids in a Standardized Eurycoma longifolia Extract (Fr 2) on the Bioavailability and Pharmacokinetic Properties, and their Implications for Oral Antimalarial Activity

A simple validated LC-UV method for the phytochemical analysis of four bioactive quassinoids, 13α(21)-epoxyeurycomanone (EP), eurycomanone (EN), 13α,21-dihydroeurycomanone (ED) and eurycomanol (EL) in rat plasma following oral (200 mg/kg) and intravenous administration (10 mg/kg) of a standardized extract Fr 2 of Eurycoma longifolia Jack was developed for pharmacokinetic and bioavailability studies. The extract Fr 2 contained 4.0%, 18.5%, 0.7% and 9.5% of EP, EN, ED and EL, respectively. Following intravenous administration, EP displayed a relatively longer biological half-life (t½ = 0.75 ± 0.25 h) due primarily to its lower elimination rate constant (ke) of 0.84 ± 0.26 h−1) when compared with the t½ of 0.35 ± 0.04 h and ke of 2.14 ± 0.27 h−1, respectively of EN. Following oral administration, EP showed a higher Cmax of 1.61± 0.41 μg/mL over that of EN (Cmax = 0.53 ± 0.10 μg/mL). The absolute bioavailability of EP was 9.5-fold higher than that of EN, not because of chemical degradation since both quassinoids were stable at the simulated gastric pH of 1. Instead, the higher log Kow value of EP (-0.43) contributed to greater membrane permeability over that of EN (log Kow = −1.46) at pH 1. In contrast, EL, being in higher concentration in the extract than EP, was not detected in the plasma after oral administration because of substantial degradation by the gastric juices after 2 h. Similarly, ED, being unstable at the acidic pH and together with its low concentration in Fr 2, was not detectable in the rat plasma. In conclusion, upon oral administration of the bioactive standardized extract Fr 2, EP and EN may be the only quassinoids contributing to the overall antimalarial activity; this is worthy of further investigation.

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Stereo-Selective Pharmacokinetics of Ilimaquinone Epimers Extracted from a Marine Sponge in Rats

Marine Drugs ◽

10.3390/md17030171 ◽

2019 ◽

Vol 17 (3) ◽

pp. 171 ◽

Cited By ~ 3

Author(s):

Heebin Son ◽

Keumhan Noh ◽

InWha Park ◽

MinKyun Na ◽

Sangtaek Oh ◽

...

Keyword(s):

Plasma Concentrations ◽

Elimination Rate ◽

Systemic Exposure ◽

Rat Plasma ◽

Absolute Bioavailability ◽

Anti Cancer ◽

The Stability ◽

The Individual ◽

Intravenous And Oral Administration

An ilimquinone (IQ) mixture isolated from Hippiospongia metachromia, consisting of IQ and epi-ilimaquinone (epi-IQ), exerts anti-HIV, anti-microbial, anti-inflammatory, and anti-cancer effects. An HPLC-MS/MS method was developed for simultaneous determination of the two epimers in rat plasma, separating them using a biphenyl column. Ascorbic acid is added during the sample preparation to ensure the stability of both isomers. The plasma concentrations of the isomers were monitored following intravenous and oral administration of the IQ mixture in rats as well as the individual epimers that were separately orally administered. Compare to IQ, epi-IQ was much more stable in rat plasma, likely due to its configurations of decalin. Both substances decayed in more than bi-exponential pattern, with an elimination rate constant of 1.2 h−1 for IQ and 1.7 h−1 for epi-IQ. The epi-IQ was distributed more widely than IQ by about two-fold. Consequently, the clearance of epi-IQ was greater than that of IQ by about three-fold. The oral absolute bioavailability for IQ was 38%, and, that for epi-IQ, was 13%. Although the systemic exposure of IQ was greater than that of epi-IQ by ~8.7-fold, the clearance of each isomer was similar when administered either orally or intravenously, when normalized for bioavailability. The stereo-specific behavior of the isomers appears to originate from differences in both their tissue distribution and gastrointestinal permeability.

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Pharmacokinetics of five phthalides in volatile oil of Ligusticum sinense Oliv.cv. Chaxiong, and comparison study on physicochemistry and pharmacokinetics after being formulated into solid dispersion and inclusion compound

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03289-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Peng-yi Hu ◽

Ying-huai Zhong ◽

Jian-fang Feng ◽

Dong-xun Li ◽

Ping Deng ◽

...

Keyword(s):

Oral Administration ◽

Solid Dispersion ◽

Oral Bioavailability ◽

Inclusion Compound ◽

Phosphate Buffer Solution ◽

Volatile Oil ◽

Rat Plasma ◽

Cerebrovascular Diseases ◽

Absolute Bioavailability ◽

Buffer Solution

Abstract Backgrounds The dried rhizome of Ligusticum sinense Oliv.cv. Chaxiong has been used to treat cardiovascular and cerebrovascular diseases, atherosclerosis, anemia and stroke. A high purity extract from chaxiong (VOC, brownish yellow oil) was extracted and separated. Its main components were senkyunolide A (SA, 33.81%), N-butylphthalide (NBP, 1.38%), Neocnidilide (NOL, 16.53%), Z-ligustilide (ZL, 38.36%), and butenyl phthalide (BP, 2.48%), respectively. Little is known about the pharmacokinetics of these phthalides in Chaxiong, and different preparations to improve the physicochemistry and pharmacokinetics of VOC have not been investigated. Methods At different predetermined time points after oral administration or intravenous administration, the concentrations of SA, NBP, NOL, ZL and BP in the rat plasma were determined using LC-MS/MS, and the main PK parameters were investigated. VOC-P188 solid dispersion and VOC-β-CD inclusion compound were prepared by melting solvent method and grinding method, respectively. Moreover, the physicochemical properties, dissolution and pharmacokinetics of VOC-P188 solid dispersion and VOC-β-CD inclusion compound in rats were assessed in comparison to VOC. Results The absorptions of SA, NBP, NOL, ZL and BP in VOC were rapid after oral administration, and the absolute bioavailability was less than 25%. After the two preparations were prepared, dissolution rate was improved at pH 5.8 phosphate buffer solution. Comparing VOC and physical mixture with the solid dispersion and inclusion compound, it was observed differences occurred in the chemical composition, thermal stability, and morphology. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound had a significantly higher AUC and longer MRT in comparison with VOC. Conclusion SA, NBP, NOL, ZL and BP in VOC from chaxiong possessed poor absolute oral bioavailability. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound could be prospective means for improving oral bioavailability of SA, NBP, NOL, ZL and BP in VOC.

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Pharmacological Properties of a New Antimalarial Bisthiazolium Salt, T3, and a Corresponding Prodrug, TE3

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.9.3631-3639.2005 ◽

2005 ◽

Vol 49 (9) ◽

pp. 3631-3639 ◽

Cited By ~ 18

Author(s):

Olivier Nicolas ◽

Delphine Margout ◽

Nicolas Taudon ◽

Sharon Wein ◽

Michèle Calas ◽

...

Keyword(s):

Oral Administration ◽

Antimalarial Activity ◽

Plasma Concentrations ◽

Intraperitoneal Administration ◽

Absolute Bioavailability ◽

Pharmacokinetic Parameters ◽

Pharmacological Properties ◽

Mean Values

ABSTRACT A new approach to malarial chemotherapy based on quaternary ammonium that targets membrane biogenesis during intraerythrocytic Plasmodium falciparum development has recently been developed. To increase the bioavailability, nonionic chemically modified prodrugs were synthesized. In this paper, the pharmacological properties of a bisthiazolium salt (T3) and its bioprecursor (TE3) were studied. Their antimalarial activities were determined in vitro against the growth of P. falciparum and in vivo against the growth of P. vinckei in mice. Pharmacokinetic evaluations were performed after T3 (1.3 and 3 mg/kg of body weight administered intravenously; 6.4 mg/kg administered intraperitoneally) and TE3 (1.5 and 3 mg/kg administered intravenously; 12 mg/kg administered orally) administrations to rats. After intraperitoneal administration, very low doses offer protection in a murine model of malaria (50% efficient dose [ED50] of 0.2 to 0.25 mg/kg). After oral administration, the ED50 values were 13 and 5 mg/kg for T3 and TE3, respectively. Both compounds exerted antimalarial activity in the low nanomolar range. After TE3 administration, rapid prodrug-drug conversion occurred; the mean values of the pharmacokinetic parameters for T3 were as follows: total clearance, 1 liter/h/kg; steady-state volume of distribution, 14.8 liters/kg; and elimination half-life, 12 h. After intravenous administration, T3 plasma concentrations increased in proportion to the dose. The absolute bioavailability was 72% after intraperitoneal administration (T3); it was 15% after oral administration (TE3). T3 plasma concentrations (8 nM) 24 h following oral administration of TE3 were higher than the 50% inhibitory concentrations for the most chloroquine-resistant strains of P. falciparum (6.3 nM).

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Pharmacokinetics and Tissue Distribution of a Novel Bis-Chelated Gold(I) Diphosphine Compound, Bis(2,3-bis(tert-butylmethylphosphino)Quinoxaline)Aurate(I), in Rats

Molecules ◽

10.3390/molecules24112082 ◽

2019 ◽

Vol 24 (11) ◽

pp. 2082

Author(s):

Ying Peng ◽

Huanhuan Qi ◽

Qingqing Chang ◽

Yu Zhang ◽

Weiyi Liu ◽

...

Keyword(s):

Mass Spectrometry ◽

Tissue Distribution ◽

Intravenous Administration ◽

Gradient Elution ◽

Rat Plasma ◽

Tissue Homogenate ◽

Ionization Source ◽

Pharmacokinetic Properties ◽

Rat Tissue

GC20, a novel soluble bis-chelated gold(I)−diphosphine compound, has been reported as a promising anticancer candidate. Assessing the pharmacokinetic properties of GC20 is critical for its medicinal evaluation. First, a sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and well validated to determine GC20 in rat plasma and rat tissue homogenate after one step protein precipitation. Chromatographic separation was achieved on an Angilent ZORBAX-C18 column (3.5 μm, 2.1 × 50 mm) with gradient elution and mass spectrometry was performed on a triple quadrupole in positive ion mode using an electrospray ionization source. This method was then applied to investigate the pharmacokinetics and tissue distribution of GC20 in rats after intravenous administration. The results showed that the plasma exposure of GC20 in vivo increased with increasing doses after a single dose. However, after multiple doses, a significant accumulation and a saturation at elimination were observed for GC20 in rats. Moreover, after intravenous administration, GC20 was widely distributed in various tissues, with the highest levels in the lung, spleen, liver, and pancreas, followed by the kidney and heart, while the lowest level was found in the brain. This is the first report on the pharmacokinetic properties of GC20.

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PHARMACOKINETIC PROPERTIES OF A NEW KAPPA-OPIOID ANALGESIC RU-1205 COMPOUND AT A SINGLE PERORAL ADMINISTRATION

Pharmacy & Pharmacology ◽

10.19163/2307-9266-2021-9-2-149-160 ◽

2021 ◽

Vol 9 (2) ◽

pp. 149-160

Author(s):

A. A. Spasov ◽

L. A. Smirnova ◽

O. Yu. Grechko ◽

N. V. Eliseeva ◽

Yu. V. Lifanova ◽

...

Keyword(s):

Oral Administration ◽

Analgesic Activity ◽

Half Life ◽

The Body ◽

Absolute Bioavailability ◽

Peroral Administration ◽

Pharmacokinetic Parameters ◽

Tail Flick ◽

Test Substance ◽

Pharmacokinetic Properties

The aim of the study is the investigation of the pharmacokinetic properties of the RU-1205 compound, with previously identified kappa-agonistic and analgesic effects, at a single oral administration, as well as comparison of the relationship between its pharmacokinetic and analgesic properties.Materials and methods. Pharmacokinetic parameters of RU-1205 after the oral administration at the dose of 50 mg / kg were investigated using the method of High Performance Liquid Chromatography with determination of the concentration of the compound according to the previously constructed calibration schedule. The indices of the area under the pharmacokinetic curve, clearance, half-life, residence time of the drug molecule in the body, a total (apparent) volume of distribution, as well as the indicator of absolute bioavailability, were calculated. The tissue distribution and excretion of RU-1205 were studied.Potential metabolites of RU-1205 were predicted using the PALLAS 3.00 program. The study of the analgesic activity was carried out on a model of central somatogenic pain with electricalstimulation, with the dynamics assessment of the voltage amplitude of the corresponding reaction of the "tail-flick" reflex.Results. The compound under study is rapidly adsorbed from the gastrointestinal tract, reaching a maximum concentration by the end of the first hour of the study, and is determined in plasma within 12 hours. Its half-life is 17.7 hours. The absolute oral bioavailability is 37.3%. It was found out that the compound is withdrawn within 3-4 days. The main route of excretion is extrarenal. Biotransformation of a substance probably proceeds mainly with the formation of oxidized forms of the initial molecule by reactions of the first phase of metabolic transformation. The analgesic effect is long-lasting: it starts after 15 minutes and lasts for 12 hours with flattening of the curve by the 8th hour.Conclusion. When administered orally, the test substance undergoes a long process of elimination, has the greatest tropism for the elimination organs and undergoes active biotransformation processes in the body of animals. As a result of it, active metabolic products with an analgesic activity are, possibly, formed.

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Pharmacokinetics of palmatine in rat after oral and intravenous administration by UPLC-MS/MS

Acta Chromatographica ◽

10.1556/1326.2020.00712 ◽

2020 ◽

pp. 1-5

Author(s):

Jianbo Li ◽

Yujie Hu ◽

Yajin Wu ◽

Tiantian Feng ◽

Congcong Wen ◽

...

Keyword(s):

Intravenous Administration ◽

Water Solubility ◽

Multiple Reaction Monitoring ◽

Internal Standard ◽

Gradient Elution ◽

Rat Plasma ◽

Precipitation Method ◽

Absolute Bioavailability ◽

Limit Of Quantification ◽

Surgical Infection

Abstract Palmatine is a compound with good water solubility extracted from Coptis chinensis, Fibraurea recisa Pierre, Cortex Phellodendri Chinensis. Palmatine has good antibacterial activity and mainly used for the treatment of bacterial dysentery, gynecological inflammation, surgical infection, and conjunctivitis. It has anti-diabetic, anti-oxidant, and cognitive-enhancing activities. In this study, we used UPLC-MS/MS to determinate palmatine in rat plasma, and investigated its pharmacokinetics. Coptisine was utilized as an internal standard (IS), and acetonitrile precipitation method was used to process the plasma samples. Chromatographic separation was achieved using a UPLC BEH C18 column using mobile phase of acetonitrile- 0.1% formic acid with gradient elution. Electrospray ionization (ESI) tandem mass spectrometry in multiple reaction monitoring (MRM) mode with positive ionization was applied. The results indicated that within the range of 1–500 ng/mL, linearity of palmatine in rat plasma was acceptable (r > 0.995), and the lower limit of quantification (LLOQ) was 1 ng/mL. Intra-day and inter-day precision RSD of palmatine in rat plasma were less than 14%. Accuracy range was between 93.7 and 107.1%, and matrix effect was between 101.6 and 109.4%. The method was successfully applied in the pharmacokinetics of palmatine in rats after oral and intravenous administration. The absolute bioavailability of the palmatine was 15.5% in rats.

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Synthesis, Antimalarial Evaluation and SAR Study of Some 1,3,5-Trisubstituted Pyrazoline Derivatives

Letters in Organic Chemistry ◽

10.2174/1570178616666190212145754 ◽

2019 ◽

Vol 16 (10) ◽

pp. 807-817 ◽

Cited By ~ 1

Author(s):

Shilpy Aggarwal ◽

Deepika Paliwal ◽

Dhirender Kaushik ◽

Girish Kumar Gupta ◽

Ajay Kumar

Keyword(s):

Antimalarial Activity ◽

Analysis Data ◽

Docking Study ◽

Maximum Activity ◽

Elemental Analysis Data ◽

Mass Spectral ◽

Structure Activity ◽

Pharmacokinetic Properties ◽

Sar Study

The synthesis of a novel series of 1,3,5-trisubstitiuted pyrazoline was achieved by refluxing chalcone derivative with different heteroaryl hydrazines. The newly synthesized compounds were characterized by 1H NMR, 13CNMR, mass spectral and elemental analysis data. The synthetic series of novel pyrazoline hybrids was screened for in vitro schizont maturation assay against chloroquine sensitive 3D7 strain of Plasmodium falciparum. Most of the compounds showed promising in vitro antimalarial activity against CQ sensitive strain. The preliminary structure-activity relationship study showed that quinoline substituted analog at position N-1 showed maximum activity followed by benzothiazole substitution, while phenyl substitution lowers the antimalarial activity. The observed activity was persistent by the docking study on P. falciparum cystein protease falcipain-2. The pharmacokinetic properties were also studied using ADME prediction.

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Simultaneous Determination of Imatinib and N-Desmethyl Imatinib in Rat Plasma and Tissues Using LC-MS/MS

Current Pharmaceutical Analysis ◽

10.2174/1573412913666170821124952 ◽

2019 ◽

Vol 15 (2) ◽

pp. 121-129

Author(s):

Zhi Rao ◽

Bo-xia Li ◽

Yong-Wen Jin ◽

Wen-Kou ◽

Yan-rong Ma ◽

...

Keyword(s):

Bone Marrow ◽

Oral Administration ◽

Parent Drug ◽

Gradient Elution ◽

Biological Tissues ◽

Rat Plasma ◽

Running Water ◽

Liver And Kidney ◽

The Brain

Background: Imatinib (IM) is a chemotherapy medication metabolized by CYP3A4 to Ndesmethyl imatinib (NDI), which shows similar pharmacologic activity to the parent drug. Although methods for determination of IM and/or NDI have been developed extensively, only few observations have been addressed to simultaneously determine IM and NDI in biological tissues such as liver, kidney, heart, brain and bone marrow. Methods: A validated LC-MS/MS method was developed for the quantitative determination of imatinib (IM) and N-desmethyl imatinib (NDI) from rat plasma, bone marrow, brain, heart, liver and kidney. The plasma samples were prepared by protein precipitation, and then the separation of the analytes was achieved using an Agilent Zorbax Eclipse Plus C18 column (4.6 × 100 mm, 3.5 µm) with gradient elution running water (A) and methanol (B). Mass spectrometric detection was achieved by a triplequadrupole mass spectrometer equipped with an electrospray source interface in positive ionization mode. Results: This method was used to investigate the pharmacokinetics and the tissue distributions in rats following oral administration of 25 mg/kg of IM. The pharmacokinetic profiles suggested that IM and NDI are disappeared faster in rats than human, and the tissue distribution results showed that IM and NDI had good tissue penetration and distribution, except for the brain. This is the first report about the large penetrations of IM and NDI in rat bone marrow. Conclusion: The method demonstrated good sensitivity, accuracy, precision and recovery in assays of IM and NDI in rats. The described assay was successfully applied for the evaluation of pharmacokinetics and distribution in the brain, heart, liver, kidney and bone marrow of IM and NDI after a single oral administration of IM to rats.

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