The clinical effects of flecainide on ventricular premature contractions and its pharmacokinetics.
Tomohiro KanazawaMamoru MiuraWataru SasakiKen KadowakiToshihide ShuMakiko HOMMAMasato HayashiShinitsu SatoKatsuo UnnoToshio SuzukiHitoshi Tada
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Abstract:
In order to determine the relationship between efficacy and plasma level of flecainide in ventricular premature contractions (VPC), a study was carried out through multipleadministration method in 15 patients with VPC at dose level of 50mg b.i.d., 100mg b.i.d., or 150mg b.i.d. The results of this study were as follows.1) Flecainide was effective in 50% of patients at 50mg b.i.d. and all patients at 100 mg b.i.d. and 150mg b.i.d. Judging from the supression ratio of VPC by flecainide, the dose level from 50mg b.i.d. to 100mg b.i.d. seems to be appropriate for clinical applications.2) The minimum effective plasma level may be placed at 200ng/ml, and a reliable suppressive effect on VPC can be expected of flecainide at plasma level of 400ng/ml or more.3) Plasma level at steady state increased dose dependently up to 100mg b.i.d., though the plasma level at 150mg b.i.d. was greatly elevated to the extent of 1, 000ng/ml or more.4) Six laboratory data in 3 patients showed abnormal values, but the elevations in GOT, GPT and BUN seemed to have slight if any relationship to the treatment. The PQ and QTc intervals on the electrocardiogram were prolonged significantly.Therefore, it may be concluded that flecainide is a useful drug for the treatment of VPC and that 100mg b.i.d. is suitable as a usual clinical dose.Keywords:
Flecainide
Plasma levels
Pharmacodynamics
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A study on pharmacokinetics of ponazuril in piglets was conducted after a single oral dose of 5.0 mg/kg b.w. Plasma concentrations were measured by high‐performance liquid chromatography assay with UV detector at 255‐nm wavelength. Pharmacokinetic parameters were derived by use of a standard noncompartmental pharmacokinetic analysis. Samples from six piglets showed good plasma concentrations of ponazuril, which peaked at 5.83 ± 0.94 μ g/mL. Mean ± SD area under the plasma concentration–time curve was 1383.42 ± 363.26 h/ μ g/mL, and the elimination half‐life was 135.28 ± 19.03 h. Plasma concentration of ponazuril peaked at 42 h (range, 36–48 h) after administration and gradually decreased but remained detectable for up to 33 days. No adverse effects were observed during the study period. The results indicate that ponazuril was relatively well absorbed following a single dose, which makes ponazuril likely to be effective in swine.
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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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OBJECTIVE To determine the plasma concentration and pharmacokinetics of gatifloxacin in healthy voluntees.METHODS The plasma concentration of gatifloxacin was determined by HPLC with the detection wavelength of 293 nm . Its pharmacokinetics was studied after oral administration of a single dose of 400mg to healthy voluntees.RESULTS The linear range was 0.057 ～ 5.22 mg ·L -1 , recovery was between 97.12% ～ 105.56% ,within day and between day RSD was less than 15%.The drug time curve after oral dose of 400 mg gatifloxacin in 10 male voluntees fitted to a two conpartment model.The main pharmacokinetic parameters of gatifloxacin were as follows: T max was 1.97 h ; C max was 3.01 mg ·L -1 ; t 1/2(β) was 9.83 h ;AUC was 28.77 mg ·h·L -1 .CONCLUSIONS The HPLC we developed for gatifloxacin determination is simple and is suitable for plasma drug concentration monitoring and human pharmacokinetic research.
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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.
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To develop a HPLC method for the determination of plasma concentration of oridonin (ORI) and study the pharmacokinetics of ORI in mice.Blood was sampled from mice which were injected ORI by 10 mg x kg(-1) at different time intervals, and the concentration of ORI was determined by HPLC. The pharmacokinetic parameters were accessed by 3P97.The calibration curve was linear (r = 0.998 7) within the range of 0.202-20.0 mg x L(-1) for ORI in plasma. The average recoveries were more than 93%. The within-day and between-day precisions were no more than 9%. After i.v. oridonin in mice, the plasma concentration-time course fitted well to two-compartment model. The pharmacokinetic equation was C = 16.192 5e(-0.554 6t) + 5.475 7e(-0.016 3t). The pharmacokinetic parameters were below: t1/2alpha 1.249 9 min, t1/2beta 42.638 4 min, K21 0.152 3 min(-1), K12 0.359 3 min(-1), K10 0.0592 min(-1), AUC 366.035 0 microg x min x mL(-1), CL 0.0273 L x min(-1) x kg(-1), V(c)0.461 5 L x kg(-1).The method can be used to determine the concentration and to investigate the pharmacokinetics of ORI in mice. ORI was absorbed and distributed very fast in mice. The effect of ORI was rapid. The elimination was the main process.
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P-glycoprotein (P-gp) is an ATP-dependent efflux membrane transporter involved in many drug pharmacokinetics in humans. Decreasing its expression could enhance the bioavailability of substrates as digoxin. We have recently found that human recombinant interleukin-2 (rIL2) in vivo decreases P-gp expression in intestine and brain of mice and modifies oral digoxin pharmacokinetics. The aim of the study was to evaluate the involvement of bioavailability in the rIL2 pretreatment effect on digoxin pharmacokinetics by comparing oral and i.v. digoxin pharmacokinetics before and after rIL2 pretreatment (10 μg/kg). We also tried to show the possible effect of a low rIL2 dose (1 μg/kg) pretreatment on oral digoxin pharmacokinetics. First, adult Swiss mice received a single oral or i.v. dose of digoxin (0.03 mg/kg). Two weeks later, the same animals were treated by rIL2 i.p. twice a day (10 μg/kg) for 4 days and received digoxin again at day 5. As well, another group received oral digoxin (0.03 mg/kg) with a 1 μg/kg rIL2 pretreatment. Blood was collected after digoxin administration with and without rIL2 pretreatment. Digoxin pharmacokinetics were described by a one-compartment model. The 10 μg/kg rIL2 pretreatment did not modify i.v. digoxin pharmacokinetics, whereas oral digoxin pharmacokinetics were significantly modified by the 10 μg/kg rIL2 pretreatment and not by the 1 μg/kg rIL2 pretreatment. The decrease of P-gp activity, caused by rIL2 (10 μg/kg), increased digoxin bioavailability. An increase in exposure and intracellular level of drugs is expected from rIL2 pretreatment.
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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.
Pentoxifylline
Active metabolite
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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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Objective:To study the pharmacokinetics of xuesaitong tablet in dog plasma.Methods:6 dogs received single-oral-dose xuesaitong tablets and plasma concentrations were determined by HPLC.Results:The main pharmacokinetics parameters of xuesaitong tablets were that tmax was(56.7±5.2) min,Cmax was(15.49±3.14) ng/μL,t1/2 was(55.66±13.64) min,and AUC(0→4h) was(1543.93±157.07) ng·min/μl.Conclusion:The method is highly sensitive,rapid,simple and specific enough to determine pharmacokinetics.
Plasma levels
Oral dose
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