Pharmacokinetics of oxaprozin in women receiving conjugated estrogen
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1,4‐Diethynylbenzene was used as conjugated all‐carbon and rigid spacer between the 2‐, 3‐ and 4‐positions of two 1‐methylquinolinium rings. Thus, for a systematic study, a series of dicationic salts with 2,2‐, 3,3‐, 4,4‐, 3,2‐, and 3,4‐interconnections of the two positive charges was prepared, in which all even‐numbered substitution patterns are conjugated, and all odd‐numbered substitution patterns are cross‐conjugated. As a consequence, conjugated/conjugated, cross‐conjugated/cross‐conjugated, and conjugated/cross‐conjugated dications have been prepared. The different combinations result in considerably different charge distributions of the positive charges within the π‐electron systems according to the rules of resonance which translate into different DFT‐calculated frontier orbital profiles and spectroscopic properties such as 13 C NMR chemical shifts, IR and Raman absorptions, and the measured as well as calculated UV/Vis spectra.
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Pharmacodynamics
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Abstract The 13 C NMR spectra of several conjugated polyyne‐aldehydes and ketones are compared with those of the corresponding alcohols. All data show considerable effects similar to those observed in conjugated polyenes.
Carbon fibers
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Drug-drug interaction (DDI) potentials of lusutrombopag, a thrombopoietin receptor agonist, on the activity of cytochrome P450 (CYP) 3A and of cyclosporine, which inhibits P-glycoprotein and breast cancer resistance protein, on lusutrombopag pharmacokinetics were assessed via clinical studies and physiologically based pharmacokinetic (PBPK) modeling.The effect of lusutrombopag on midazolam (a CYP3A probe substrate) pharmacokinetics was assessed in 15 healthy subjects receiving a single midazolam 5-mg dose with or without coadministration of lusutrombopag 0.75 mg for 6 days (first dose: 1.5-mg dose). The effect of cyclosporine on lusutrombopag pharmacokinetics was assessed in 16 healthy subjects receiving a single lusutrombopag 3-mg dose with or without a single cyclosporine 400- to 600-mg dose. PBPK modeling was employed to extrapolate the effect of lusutrombopag at the clinical dose (3 mg once daily) on midazolam pharmacokinetics.In the clinical study, mean ratios (90% confidence intervals [CIs]) of with/without lusutrombopag for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of midazolam were 1.01 (0.908-1.13) and 1.04 (0.967-1.11), respectively, indicating no effect of lusutrombopag on midazolam pharmacokinetics. PBPK modeling suggested no effect of lusutrombopag at the clinical dose on midazolam pharmacokinetics. Mean ratios (90% CIs) of with/without cyclosporine for lusutrombopag Cmax and AUC were 1.18 (1.11-1.24) and 1.19 (1.13-1.25), respectively, indicating a slight increase in lusutrombopag exposure.In consideration with in vitro data, the in vivo and in silico results suggested no clinically significant DDI potential of lusutrombopag with other medical products via metabolic enzymes and transporters.
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Background/Aim. Methotrexate (MTX) plays a significant role in the treatment of various diseases, but the toxicity remains the main issue of its use, especially when administered in high doses. Considering altered pharmacokinetics of MTX as a factor strongly implicated in the large interpatient variability and unexpected toxicity in certain patients, the accurate description of MTX pharmacokinetic behaviour of both low and high doses is of the utmost importance. Therefore, the objective of this study was to determine the pharmacokinetics of MTX after intravenous (iv) administration in ascending doses of 5, 40, 80 and 160 mg/kg in rats and to select the appropriate mathematical model describing MTX pharmacokinetics. Methods. Plasma concentrations of MTX were measured using the liquid chromatography - mass spectrometry (LC/MS) method. Pharmacokinetic parameters were calculated by non-compartmental and two-compartmental integer-order analyses. Results. MTX showed linear pharmacokinetics following iv administration up to the dose of 80 mg/kg. The administration of a high dose of MTX (160 mg/kg) resulted in the similar pharmacokinetic behaviour as when applied in the twice lower dose (80 mg/kg), which can be explained by dose-dependent changes in the expression of solute carrier (SLC) and ATP binding cassette (ABC) transport proteins and intracellular metabolism. Furthermore, the classical two-compartment model could not explain the pharmacokinetics of MTX in a small percentage of experimental animals, which opens up new strategies for the use of fractional order pharmacokinetic models in MTX therapy optimisation. Conclusion. These results of pharmacokinetic analyses may be helpful in adjusting the dosage regimen of MTX, but the application of novel pharmacokinetic models, such as those based on fractional calculus, is still needed in the process of MTX therapy optimisation.
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Introduction: Niclosamide (Nc) is an FDA-approved anthelmintic drug that was recently identified in a drug repurposing screening to possess antiviral activity against SARS-CoV-2. However, due to the low solubility and permeability of Nc, its in vivo efficacy was limited by its poor oral absorption. Method: The current study evaluated a novel prodrug of Nc (PDN; NCATS-SM4705) in improving in vivo exposure of Nc and predicted pharmacokinetic profiles of PDN and Nc across different species. ADME properties of the prodrug were determined in humans, hamsters, and mice, while the pharmacokinetics (PK) of PDN were obtained in mice and hamsters. Concentrations of PDN and Nc in plasma and tissue homogenates were measured by UPLC-MS/MS. A physiologically based pharmacokinetic (PBPK) model was developed based on physicochemical properties, pharmacokinetic and tissue distribution data in mice, validated by the PK profiles in hamsters and applied to predict pharmacokinetic profiles in humans. Results: Following intravenous and oral administration of PDN in mice, the total plasma clearance (CLp) and volume of distribution at steady-state (Vdss) were 0.061-0.063 L/h and 0.28-0.31 L, respectively. PDN was converted to Nc in both liver and blood, improving the systemic exposure of Nc in mice and hamsters after oral administration. The PBPK model developed for PDN and in vivo formed Nc could adequately simulate plasma and tissue concentration-time profiles in mice and plasma profiles in hamsters. The predicted human CLp/F and Vdss/F after an oral dose were 2.1 L/h/kg and 15 L/kg for the prodrug respectively. The predicted Nc concentrations in human plasma and lung suggest that a TID dose of 300 mg PDN would provide Nc lung concentrations at 8- to 60-fold higher than in vitro IC50 against SARS-CoV-2 reported in cell assays. Conclusion: In conclusion, the novel prodrug PDN can be efficiently converted to Nc in vivo and improves the systemic exposure of Nc in mice after oral administration. The developed PBPK model adequately depicts the mouse and hamster pharmacokinetic and tissue distribution profiles and highlights its potential application in the prediction of human pharmacokinetic profiles.
ADME
Niclosamide
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Objective To study the pharmacokinetics and tissue distribution of Chuanhuning-emulsion( CHE) in rats. Methods The commercial ordinary Chuanhuning injection was used as the reference( CHR) to evaluate the pharmacokinetics and tissue distribution of CHE. After intravenous administration of CHE or CHR( 40 mg / kg) in rats,the concentration of dehydroandrographolide succinate( DAS,the active ingredients of CHE in vivo) was detected by LC-MS / MS. Pharmacokinetic analysis was performed using WinNolin 6. 2. Tissue distribution and targeting were evaluated through tissue concentrations. Results First,a suitable detection method was set up to study the pharmacokinetics of DAS. Second,there was no significant difference between CHR and CHE in the pharmacokinetic parameters. However,the concentrations of DAS in lungs of CHE group were higher than those in CHR group even at 2 h after iv administration of CHE or CHR. Conclusion CHE has a similar pharmacokinetic profile as CHR in rats. Furthermore,the cumulation of DAS in lungs is increased,which illustrates that CHE could enhance DAS targeted in lungs.
Tissue distribution
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Abstract Reaction of the title heterocycle (I) with 1,3‐butadienes such as (II) or (V) affords conjugated and/or non‐conjugated cyclopentenones such as (III), (IV), (VII) or (VIII) in a novel one‐pot procedure.
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Abstract The aim of this study was to develop pharmacokinetic models for pentoxifylline (PTX) and the R(-)-enantiomer of the PTX metabolite 1, lisofylline (LSF), in order to identify some factors influencing the absorption of these compounds from the intestines and to clarify mechanisms involved in their non-linear pharmacokinetics. Serum samples were collected after oral and intravenous administration of PTX and LSF to male CD-1 mice at two different doses. In addition, both compounds under investigation were coadministered with a modulator of drug transporters, verapamil, and an inhibitor of cytochrome P450 (CYP) 3A4, ketoconazole. Pharmacokinetic analysis revealed that a one-compartment model with Michaelis-Menten type absorption and elimination best described the pharmacokinetics of PTX, whereas the LSF concentration-time data were adequately fitted to a two-compartment model with a first-order absorption and Michaelis-Menten type elimination process. Both coadministered compounds significantly decreased the area under the concentration-time curve from 0 to 60 min calculated for PTX and increased the value of this parameter for LSF. The results of this study indirectly suggest that saturation of drug transport across intestinal cells and elimination from the central compartment may be responsible for the non-linear pharmacokinetics of PTX, whereas in the case of LSF, the dose dependency in the pharmacokinetics is solely related to the elimination from the central compartment. It seems that the observed changes in PTX and LSF concentrations after coadministration with verapamil and ketoconazole may be clinically significant, especially after chronic treatment, however further studies are necessary to assess the importance of these interactions in humans.
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5-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-pyridin-3-yl]-3-ethyl-2-(2-methoxy-ethyl)-2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one (UK-369,003) is a phosphodiesterase-5 inhibitor in clinical development at Pfizer. UK-369,003 is predominantly metabolized by cytochrome P450 3A4 and is also a substrate for the efflux transporter P-glycoprotein. The pharmacokinetics of UK-369,003 has been profiled after oral administration of 1 to 800 mg of an immediate release formulation to healthy volunteers. Nonlinearity was observed in the systemic exposure at doses of 100 mg and greater. In addition, the pharmacokinetics of UK-369,003 has also been investigated after oral administration of the more therapeutically attractive modified release formulation. Systemic exposure was prolonged with the modified release formulation, but bioavailability was reduced in comparison with that of the immediate release formulation. Physiologically based pharmacokinetic modeling strategies are commonly used in drug discovery and development. This work describes application of the physiologically based pharmacokinetic software GastroPlus to understand the pharmacokinetics of UK-369,003. The impact of gut wall and hepatically mediated CYP3A4 metabolism, in addition to the actions of P-glycoprotein, in causing the nonlinear pharmacokinetics of the immediate release formulation and the reduced bioavailability of the modified release form, was investigated. The model accurately described the systemic exposure of UK-369,003 after intravenous and both immediate and modified release oral administration and suggested that CYP3A4 is responsible for the majority of the nonlinearity in systemic exposure observed after administration of the immediate release form. Conversely, the reduced bioavailability of the modified release formulation is believed to be caused by incomplete release from the device, incomplete absorption of released drug, and, to a lesser extent, CYP3A4 metabolism.
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