PHARMACOKINETIC DRUG INTERACTION BETWEEN CLOPIDOGREL AND ESOMEPRAZOLE IN ADULT HEALTHY MALE VOLUNTEERS

Objective: Proton pump inhibitors (PPIs) are known to impair cytochrome P2C19 mediated activation of clopidogrel, the antiplatelet agent used for cardiovascular risk prevention. Esomeprazole is an optical isomer of omeprazole with better efficacy and tolerability than conventional PPIs. Esomeprazole is often co-administered with clopidogrel considering the risk of associated gastrointestinal bleeding. This study was designed to determine the effect of esomeprazole on the mean pharmacokinetic profile clopidogrel.Methods: A total of 14 adult healthy male participants who volunteered participation were enrolled, randomized equally into two cross-over sequences, dosed with clopidogrel and clopidogrel + esomeprazole in respective periods. Blood samples were collected through antecubital or forearm vein indwelling catheter. Concentration of clopidogrel parent prodrug in isolated plasma was determined using validated sensitive liquid chromatography – mass spectrometry. Pharmacokinetic modeling was carried out using PKSOLVER add-in for Microsoft Excel.Results: The pharmacokinetic profile of clopidogrel was non-significantly altered by esomeprazole. Statistically significant difference in peak plasma concentration, apparent volume of distribution, and clearance of clopidogrel was observed only during period II in participants co-dosed with esomeprazole (p=0.0483, 0.0011, and 0.0015, respectively). All other primary and secondary pharmacokinetic parameters displayed minor alterations during either period (p>0.05).Conclusion: The non-significant alteration of clopidogrel pharmacokinetics by esomeprazole can be potentiated by underlying predisposing factors such as the presence of CYP2C19 allelic variants and increasing the risk of cardiovascular events. Hence, co-administration of clopidogrel and esomeprazole should be under clinical monitoring and is not recommended in poor responders of antiplatelet therapy with clopidogrel.

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The effects of oral administration of Cola nitida on the pharmacokinetic profile of metoclopramide in rabbits

BMC Pharmacology and Toxicology ◽

10.1186/s40360-019-0379-6 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Cecilia Nwadiuto Amadi ◽

Wisdom Izuchukwu Nwachukwu

Keyword(s):

Drug Interaction ◽

Plasma Concentration ◽

Oral Administration ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Elimination Rate ◽

Area Under The Curve ◽

Pharmacokinetic Profile ◽

Pharmacokinetic Parameters ◽

Cola Nitida

Abstract Background Cola nitida is commonly chewed in many West African cultures to ease hunger pangs and sometimes for their stimulant and euphoriant qualities. Metoclopramide is a known substrate for P-gp, SULT2A1 and CYP2D6 and studies have revealed that caffeine- a major component of Cola nitida can induce P-glycoprotein (P-gp), SULT2A1 and SULT1A1, hence a possible drug interaction may occur on co-administration. The aim of this study was to investigate the pharmacokinetic interactions of Cola nitida and metoclopramide in rabbits. Methods The study was performed in two stages using five healthy male rabbits with a 1-week washout period between treatments. Stage one involved oral administration of metoclopramide (0.5 mg/kg) alone while in the second stage, metoclopramide (0.5 mg/kg) was administered concurrently with Cola nitida (0.7 mg/kg). Blood samples were collected after each stage at predetermined intervals and analyzed for plasma metoclopramide concentration using HPLC. Results Compared with control, the metoclopramide/Cola nitida co-administration produced a decrease in plasma concentration of metoclopramide at all the time intervals except at the 7th hour. The following pharmacokinetic parameters were also decreased: area under the curve (51%), peak plasma concentration (39%), half-life (51%); while an increase in elimination rate constant (113%) and clearance rate (98%) were noted indicating rapid elimination of the drug. A minimal decrease in absorption rate (10%) was also observed. Conclusions The results of this study reveal a possible herb-drug interaction between Cola nitida and metoclopramide.

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ALTERATION OF PHARMACOKINETIC PARAMETERS OF PENTOXIFYLLINE USING NATURAL MUCOADHESIVE POLYMERS

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2020v12i1.36080 ◽

2019 ◽

pp. 153-157

Author(s):

GNANASEKARAN JOHN SELVARAJ ◽

ARUL BALASUBRAMANIAN ◽

KOTHAI RAMALINGAM

Keyword(s):

Drug Concentration ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Fold Increase ◽

Ocimum Basilicum ◽

Plasma Drug Concentration ◽

Pharmacokinetic Parameters ◽

Plasma Drug ◽

Time Curve ◽

Significant Difference

Objective: The present study was aimed to alter the pharmacokinetic parameters of the drug pentoxifylline using a novel natural mucoadhesive polymer from two different plants, Manilkara zapotta Linn and Ocimum basilicum Linn. Methods: The polymer was isolated and six batches of mucoadhesive tablets of pentoxifylline was formulated with 3 different concentrations of each polymer. The best formulation from each of the polymer was selected and administered to rabbits and the plasma drug concentration was compared with the marketed formulation. The pharmacokinetic parameters such as such as Cmax, tmax, AUC, AUMC, λz, t1/2, and MRT were determined. Results: The plasma drug concentration vs time curve shows the extended-release of pentoxifylline when compared with the conventional marketed formulation. The results show that there is no change in the peak plasma concentration, but the significant difference was observed in t½, which showed approximately 2.5 fold increase from 2.44 to 6.87 h and the AUC showed five-fold increase from 22.40 to 117.19 μg*h/ml, and other pharmacokinetic parameters, when compared with the marketed formulation. Conclusion: The isolated polymer from the plants Manilkara zapotta Linn. and Ocimum basilicum Linn can be used as a carrier for developing mucoadhesive formulations and it alter the pharmacokinetic of pentoxifylline positively.

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Pharmacokinetics of Moxifloxacin in A 5/6th Nephrectomized Rat Model

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2009.2.4.9 ◽

1970 ◽

Vol 2 (4) ◽

pp. 748-755

Author(s):

Hariprasath Kothandam ◽

Venkatesh Palaniyappan ◽

Sudheer Babu Idpuganti ◽

Umamaheswari Muthusamy

Keyword(s):

Renal Failure ◽

Rat Model ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Area Under The Curve ◽

Laboratory Animals ◽

Pharmacokinetic Parameters ◽

Control Group ◽

Significant Difference ◽

And Control

Moxifloxacin (MFLX) is a new 8-methoxyfluoroquinolone derivative with a broad spectrum of antibacterial activity. MFLX at doses of 200 and 400 mg was selected to conduct the pharmacokinetic study and the drug was given orally to control and nephrectomized rats. A 5/6th nephrectomized rat model was used in this study. The drug levels in the plasma were determined using a spectrofluorimetric assay. The pharmacokinetic parameters viz. peak plasma concentration (Cmax) and area under the curve (AUC0-8) of the nephrectomized and control rats were compared. The Cmax for both 200 and 400 mg dose of MFLX in nephrectomized rats showed significant difference(P<0.001) from the control group, which reveals the changes in the Cmax of MFLX in renal failure. The AUC0-8 for both 200 and 400 mg dose of MFLX in nephrectomized rats differ significantly (P<0.001) from sham operated control group, which implies the variation in MFLX availability in altered renal function. The AUC0-8 for 400 mg dose of MFLX in nephrectomized rats differ significantly from 200 mg dose of MFLX in nephrectomized group, which reveals that in higher dose, MFLX shows an abrupt increase in the drug availability in renal failure. It is conclude that preclinical drug monitoring of moxifloxacin in laboratory animals can be performed by using 5/6th nephrectomized rat models for determining the dose of MFLX for kidney failured patients. Various pharmacokinetic parameters determined differed in nephrectomised rats when compared to the control.

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Emulsification by TPGS or Quillaja Extract Increased Absorption and Affected Metabolism of Berberine in Humans

Current Developments in Nutrition ◽

10.1093/cdn/nzab037_091 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 381-381

Author(s):

Yavuz Yagiz ◽

Gary Wang ◽

Liwei Gu

Keyword(s):

Peak Plasma ◽

Peak Plasma Concentration ◽

Area Under The Curve ◽

Total Content ◽

Compartment Model ◽

Analysis Of Covariance ◽

High Tech ◽

Pharmacokinetic Parameters ◽

Funding Sources ◽

Human Volunteers

Abstract Objectives Berberine is a botanical alkaloid used widely for the prevention of several diseases. However, the absorption rate of berberine is less than 1% in human. The objectives of this study were to determine whether emulsification by TPGS or Quillaja extract affect the absorption and metabolism of orally ingested berberine in human volunteers. Methods Twelve healthy subjects (7 male and 5 females, 21–50-year-old) participated this study. Each subject received 800 mg berberine in a powder form or emulsified with TPGS or Quillaja extract using a randomized crossover design with one-week washout period. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after dose. Plasma was hydrolyzed with glucuronidase and sulfatase before total content of berberine and its metabolites were analyzed on LC/MS/MS. Free forms of metabolites were determined in plasma without hydrolysis. Pharmacokinetic parameters were calculated using a non-compartment model before they were compared by analysis of covariance. Results The area under the curve (AUC) and peak plasma concentration (Cmax) of berberine was 6.6 μM.hr and 0.9 μM in participants received berberine powder. They were increased to 18.3 μM.hr and 4.5 μM by TPGS emulsification and 28 μM.hr and 5.1 μM by Quillaja extract emulsification, respectively. Berberrubine and demethylberberine were major metabolites of berberine. The AUC of free Berberrubine and demethylberberine was increased by 1.9 fold and 1.6 fold by TPGS and 5.9 folds and 2.7 folds by Quillaja extract, respectively, compared to berberine powder. Participants received berberine powder had AUC of 254 μM.hr and Cmax of 33 μM for total berberrubine. TPGS emulsification increased these values to 425 μM.hr and 54 μM, while Quillaja extract increased them to 341 μM.hr and 44 μM, respectively. Significant increases of AUC and Cmax were also observed for total demethylberberine by TPGS or Quillaja extract emulsification. Conclusions Emulsification of berberine with TPGS or Quillaja extract significantly increased the absorption of berberine and its metabolites in human compared to berberine supplement without emulsifiers. Funding Sources Florida High Tech Corridor Council and Designs for Health.

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Antinociceptive Interaction and Pharmacokinetics of the Combination Treatments of Methyleugenol Plus Diclofenac or Ketorolac

Molecules ◽

10.3390/molecules25215106 ◽

2020 ◽

Vol 25 (21) ◽

pp. 5106

Author(s):

Héctor Isaac Rocha-González ◽

María Elena Sánchez-Mendoza ◽

Leticia Cruz-Antonio ◽

Francisco Javier Flores-Murrieta ◽

Xochilt Itzel Cornelio-Huerta ◽

...

Keyword(s):

Peak Plasma ◽

Peak Plasma Concentration ◽

Dependent Manner ◽

Analgesic Drugs ◽

Isobolographic Analysis ◽

Combination Treatments ◽

Significant Difference ◽

Effective Doses ◽

Inflammatory Drugs ◽

Dose Dependent

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the main types of drugs used to treat pain, they have several adverse effects, and such effects can be reduced by combining two analgesic drugs. The aim of this study was to evaluate the nociceptive activity of methyleugenol combined with either diclofenac or ketorolac, and determine certain parameters of pharmacokinetics. For the isobolographic analysis, the experimental effective dose 30 (ED30) was calculated for the drugs applied individually. With these effective doses, the peak plasma concentration (Cmax) was found and the other parameters of pharmacokinetics were established. Methyleugenol plus diclofenac and methyleugenol plus ketorolac decreased licking behavior in a dose-dependent manner in phase II, with an efficacy of 32.9 ± 9.3 and 39.8 ± 9.6%, respectively. According to the isobolographic analysis, the experimental and theoretical ED30 values were similar for methyleugenol plus diclofenac, suggesting an additive effect, but significantly different for methyleugenol plus ketorolac (3.6 ± 0.5 vs. 7.7 ± 0.6 mg/kg, respectively), indicating a probable synergistic interaction. Regarding pharmacokinetics, the only parameter showing a significant difference was Cmax for the methyleugenol plus diclofenac combination. Even with this difference, the combinations studied may be advantageous for treating inflammatory pain, especially for the combination methyleugenol plus ketorolac.

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Comparative in vivo study of pure drug and fast dissolving tablets of Simvastatin

Journal of Drug Delivery and Therapeutics ◽

10.22270/jddt.v9i4-a.3508 ◽

2019 ◽

Vol 9 (4-A) ◽

pp. 490-496

Author(s):

M. Suresh Babu ◽

T. E. Gopalakrishna Murthy

Keyword(s):

Rate Constant ◽

Plasma Levels ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Elimination Rate ◽

In Vivo Studies ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Studies ◽

Pure Drug

The objective of this study was to investigate differences in the pharmacokinetic patterns between pure drug and an optimized formulation of fast dissolving tablets of Simvastatin. The formulations were administered to 2 groups of white New Zealand rabbits (n=6) following cross over design pattern and the plasma levels were measured using LC-MS/MS method. Pharmacokinetic parameters were determined for each formulation. The comparison of the plasma time curves of the dosage forms showed that each dosage form caused significant differences in the drug plasma levels. The highest mean Cmax value was observed for optimized fast dissolving tablets (68.33 ± 0.42ng/ml) compared to pure drug (27.72 ± 0.31ng/ml). The mean time taken to peak plasma concentration for (Tmax) following administration of pure drug was 11.53 ± 0.011hours, while it was 6.09 ± 0.072 hour following administration of selected optimized fast dissolving tablets.The elimination rate constant (Kel) for pure drug and optimized fast dissolving tablets were found to be 0.58 ± 0.012h-1and 0.53 ± 0.014 h-1 respectively. The absorption rate constant (Ka) for pure drug and optimized fast dissolving tablets were found to be 1.68 ± 0.01h-1and 5.53 ± 0.02h-1 respectively. The AUC0-αvalues observed with optimized fast dissolving tablets686.1.±2.07 nghr/ml in compared to pure drug values 191 ± 1.43 nghr/ml. Thus, the results of pharmacokinetic studies indicated rapid and higher oral absorption of Simvastatin when administered as its fast dissolving tablets. Both Ka and AUC were markedly increased by fast dissolving tablets. Keywords: LC-MS/MS, Simvastatin, fast dissolving, In-vivo studies, pharmacokinetic parameters.

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Pharmacokinetic Study of Modafinil in Relation to Gender and Ethnicity in Healthy Young Chinese Volunteers

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3fk5r ◽

2010 ◽

Vol 13 (3) ◽

pp. 443 ◽

Cited By ~ 3

Author(s):

Tao Guo ◽

Longshan Zhao ◽

Dong-Ya Xia

Keyword(s):

Body Weight ◽

Oral Dose ◽

High Performance ◽

Area Under The Curve ◽

Total Body Weight ◽

Apparent Volume ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Significant Difference ◽

Total Body

Purpose. The pharmacokinetics of modafinil were investigated in relation to gender and ethnicity in healthy young volunteers from Han, Mongolian, Korean, Uygur and Hui ( n = 10/group) following administration of a single 200 mg oral dose. Methods. Blood samples were collected over 48 h for the determination of plasma levels of modafinil and its acid metabolite by High performance liquid chromatography with an ultraviolet detector. Pharmacokinetic parameters were evaluated using noncompartmental methods. Results. Modafinil was well tolerated and safe at a single oral dose of 200 mg. All participants reported adverse events, none of which was serious or unexpected. The maximum plasma concentration (Cmax) and area under the curve for modafinil concentration versus time, which was extrapolated to infinity (AUC0-∞), were higher in women compared to men (p < 0.01). No gender-based difference was noted in the total body weight-normalized modafinil oral clearance. The total body weight-normalized modafinil apparent volume of distribution and the t1/2 was found to exhibit an ethnicity-based significant difference. Conclusion. The results of the current study suggest that there might be pharmacokinetic differences related to gender and ethnicity in the pharmacokinetics of modafinil.

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Simple and Accurate HPTLC-Densitometric Method for Quantification of Delafloxacin (A Novel Fluoroquinolone Antibiotic) in Plasma Samples: Application to Pharmacokinetic Study in Rats

Antibiotics ◽

10.3390/antibiotics9030134 ◽

2020 ◽

Vol 9 (3) ◽

pp. 134 ◽

Cited By ~ 3

Author(s):

Prawez Alam ◽

Muzaffar Iqbal ◽

Essam Ezzeldin ◽

Nasr Y. Khalil ◽

Ahmed I. Foudah ◽

...

Keyword(s):

Oral Administration ◽

Biological Samples ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Internal Standard ◽

Pharmacokinetic Profile ◽

Precipitation Method ◽

Therapeutic Drug ◽

Fluoroquinolone Antibiotic ◽

Hptlc Method

Delafloxacin (DLX) is a recently-approved fluoroquinolone antibiotic, which is recommended for the treatment of “acute bacterial skin and skin structure infections”. A thorough literature survey revealed only a single published method for the estimation of DLX using UPLC-MS/MS technique in biological samples. There is no high-performance thin-layer chromatography (HPTLC) method has been reported for the estimation of DLX in dosage forms and/or biological samples. Therefore, a selective, sensitive, rapid and validated HPTLC-densitometry technique has been used for the estimation of DLX in human plasma for the first time. HPTLC quantification of DLX and internal standard (IS; gatifloxacin) was carried out on glass coated silica gel 60 F254 HPTLC plates using the ternary mixture of ethyl acetate:methanol:ammonia solution 5:4:2 (%, v/v/v) as the mobile phase. Densitometric detection was done at 344 nm. The Rf values were recorded as 0.43 and 0.27 for the DLX and the IS, respectively. The linearity range of DLX was obtained as 16–400 ng/band. A simple protein precipitation method was used for the extraction of analyte from plasma using methanol. The proposed HPTLC technique was validated for “linearity, accuracy, precision, and robustness”. The proposed HPTLC technique was successfully utilized for the assessment of pharmacokinetic profile of DLX in rats after oral administration. After oral administration, the peak plasma concentration of DLX was obtained as 194.19 ng/ml in 1 h. The proposed HPTLC method could be applied in study of pharmacokinetic profile and therapeutic drug monitoring of DLX in clinical practice.

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Pharmacokinetic Study of Human Immunodeficiency Virus Protease Inhibitors Used in Combination with Amprenavir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.12.3663-3668.2001 ◽

2001 ◽

Vol 45 (12) ◽

pp. 3663-3668 ◽

Cited By ~ 20

Author(s):

Brian M. Sadler ◽

Catherine Gillotin ◽

Yu Lou ◽

Joseph J. Eron ◽

William Lang ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Steady State ◽

Protease Inhibitors ◽

Pharmacokinetic Study ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Open Label ◽

Immunodeficiency Virus

ABSTRACT In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUCss] and 37% for peak plasma concentration at steady state [C max,ss]) and increased by indinavir (33% for AUCss). Nelfinavir significantly increased amprenavir minimum drug concentration at steady state (by 189%) but did not affect amprenavir AUCss orC max,ss. Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in amprenavir steady-state pharmacokinetic parameters, relative to those for amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.

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Enhanced Oral Bioavailability of Efavirenz by Solid Lipid Nanoparticles:In VitroDrug Release and Pharmacokinetics Studies

BioMed Research International ◽

10.1155/2014/363404 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 43

Author(s):

Praveen Kumar Gaur ◽

Shikha Mishra ◽

Meenakshi Bajpai ◽

Anushika Mishra

Keyword(s):

Drug Release ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

Tween 80 ◽

Fold Increase ◽

Pharmacokinetic Profile ◽

Water Soluble ◽

Physical Parameters ◽

Solid Lipid

Solid lipid nanoparticle is an efficient lipid based drug delivery system which can enhance the bioavailability of poorly water soluble drugs. Efavirenz is a highly lipophilic drug from nonnucleoside inhibitor category for treatment of HIV. Present work illustrates development of an SLN formulation for Efavirenz with increased bioavailability. At first, suitable lipid component and surfactant were chosen. SLNs were prepared and analyzed for physical parameters, stability, and pharmacokinetic profile. Efavirenz loaded SLNs were formulated using Glyceryl monostearate as main lipid and Tween 80 as surfactant. ESLN-3 has shown mean particle size of124.5±3.2nm with a PDI value of 0.234, negative zeta potential, and 86% drug entrapment.In vitrodrug release study has shown 60.6–98.22% drug release in 24 h by various SLN formulations. Optimized SLNs have shown good stability at 40°C±2°C and75±5% relative humidity (RH) for 180 days. ESLN-3 exhibited 5.32-fold increase in peak plasma concentration (Cmax⁡) and 10.98-fold increase in AUC in comparison to Efavirenz suspension (ES).

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