Effects of Silymarin on the In Vivo Pharmacokinetics of Simvastatin and Its Active Metabolite in Rats

Herein, the effect of silymarin pretreatment on the pharmacokinetics of simvastatin in rats was evaluated. To ensure the accuracy of the results, a rapid and sensitive UPLC–MS/MS method was established for simultaneous quantification of simvastatin (SV) and its active metabolite simvastatin acid (SVA). This method was applied for studying the pharmacokinetic interactions in rats after oral co-administration of silymarin (45 mg/kg) and different concentrations of SV. The major pharmacokinetic parameters, including Cmax, tmax, t1/2, mean residence time (MRT), elimination rate constant (λz) and area under the concentration-time curve (AUC0–12h), were calculated using the non-compartmental model. The results showed that the co-administration of silymarin and SV significantly increased the Cmax and AUC0–12h of SVA compared with SV alone, while there was no significant difference with regards to Tmax and t1/2. However, SV pharmacokinetic parameters were not significantly affected by silymarin pretreatment. Therefore, these changes indicated that drug-drug interactions may occur after co-administration of silymarin and SV.

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Pharmacokinetics of intramuscularly administered aminosidine in healthy subjects.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.5.982 ◽

1997 ◽

Vol 41 (5) ◽

pp. 982-986 ◽

Cited By ~ 12

Author(s):

T P Kanyok ◽

A D Killian ◽

K A Rodvold ◽

L H Danziger

Keyword(s):

Healthy Subjects ◽

Randomized Clinical Trials ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Multiple Drug ◽

Time Data ◽

Time Curve ◽

First Order ◽

Significant Difference

Aminosidine is an older, broad-spectrum aminoglycoside antibiotic that has been shown to be effective in in vitro and animal models against multiple-drug-resistant tuberculosis and the Mycobacterium avium complex. The objective of this randomized, parallel trial was to characterize the single-dose pharmacokinetics of aminosidine sulfate in healthy subjects (eight males, eight females). Sixteen adults (mean [+/- standard deviation] age, 27.6 +/- 5.6 years) were randomly allocated to receive a single, intramuscular aminosidine sulfate injection at a dose of 12 or 15 mg/kg of body weight. Serial plasma and urine samples were collected over a 24-h period and used to determine aminosidine concentrations by high-performance liquid chromatographic assay. A one-compartment model with first-order input, first-order output, and a lag time (Tlag) and with a weighting factor of 1/y2 best described the data. Compartmental and noncompartmental pharmacokinetic parameters were estimated with the microcomputer program WinNonlin. One subject was not included (15-mg/kg group) because of the lack of sampling time data. On average, subjects attained peak concentrations of 22.4 +/- 3.2 microg/ml at 1.34 +/- 0.45 h. All subjects had plasma aminosidine concentrations below 2 microg/ml at 12 h, and all but two subjects (one in each dosing group) had undetectable plasma aminosidine concentrations at 24 h. The dose-adjusted area under the concentration-time curve from 0 h to infinity of aminosidine was identical for the 12- and 15-mg/kg groups (9.29 +/- 1.5 versus 9.29 +/- 2.2 microg x h/ml per mg/kg; P = 0.998). Similarly, no significant differences (P > 0.05) were observed between dosing groups for peak aminosidine concentration in plasma, time to peak aminosidine concentration in plasma, Tlag, apparent clearance, renal clearance, elimination rate constant, and elimination half-life. A significant difference was observed for the volume of distribution (0.35 versus 0.41 liters/kg; P = 0.037) between the 12 and 15 mg/kg dosing groups. Now that comparable pharmacokinetic profiles between dosing groups have been demonstrated, therapeutic equivalency testing via in vitro pharmacokinetic and pharmacodynamic modelling and randomized clinical trials in humans should be conducted.

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Development of a Population Pharmacokinetic Model for Parecoxib and Its Active Metabolite Valdecoxib after Parenteral Parecoxib Administration in Children

Anesthesiology ◽

10.1097/aln.0b013e31825154ef ◽

2012 ◽

Vol 116 (5) ◽

pp. 1124-1133 ◽

Cited By ~ 11

Author(s):

Bruce Hullett ◽

Sam Salman ◽

Sean J. O'Halloran ◽

Deborah Peirce ◽

Kylie Davies ◽

...

Keyword(s):

Active Metabolite ◽

Pharmacokinetic Model ◽

Inhibitory Concentration ◽

Prediction Interval ◽

Cyclooxygenase 2 ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Time Curve ◽

Concentration Time

Background Parecoxib is a cyclooxygenase-2 selective inhibitor used in management of postoperative pain in adults. This study aimed to provide pediatric pharmacokinetic information for parecoxib and its active metabolite valdecoxib. Methods Thirty-eight children undergoing surgery received parecoxib (1 mg/kg IV to a maximum of 40 mg) at induction of anesthesia, and plasma samples were collected for drug measurement. Population pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Area under the valdecoxib concentration-time curve and time above cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib were simulated. Results A three-compartment model best represented parecoxib disposition, whereas one compartment was adequate for valdecoxib. Age was linearly correlated with parecoxib clearance (5.0% increase/yr). There was a sigmoid relationship between age and both valdecoxib clearance and distribution volume. Time to 50% maturation was 87 weeks postmenstrual age for both. In simulations using allometric-based doses the 90% prediction interval of valdecoxib concentration-time curve in children 2-12.7 yr included the mean for adults given 40 mg parecoxib IV. Simulated free valdecoxib plasma concentration remained above the in vitro 50% inhibitory concentrations for more than 12 h. In children younger than 2 yr, a dose reduction is likely required due to ongoing metabolic maturation. Conclusions The final pharmacokinetic model gave a robust representation of parecoxib and valdecoxib disposition. Area under the valdecoxib concentration-time curve was similar to that in adults (40 mg), and simulated free valdecoxib concentration was above the cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib for at least 12 h.

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Limited Sampling Strategies to Estimate the Area under the Concentration-time Curve

Methods of Information in Medicine ◽

10.3414/me11-01-0071 ◽

2012 ◽

Vol 51 (05) ◽

pp. 383-394 ◽

Cited By ~ 5

Author(s):

M. Fukumoto ◽

L. Bax ◽

A. Kohno ◽

Y. Morishita ◽

H. Tsuruta

Keyword(s):

Rate Constant ◽

Elimination Rate ◽

Estimation Method ◽

Pharmacokinetic Parameters ◽

Good Precision ◽

Sampling Strategies ◽

Time Curve ◽

New Methods ◽

Limited Sampling ◽

Concentration Time

SummaryBackground: Over 100 limited sampling strategies (LSSs) have been proposed to reduce the number of blood samples necessary to estimate the area under the concentration-time curve (AUC). The conditions under which these strategies succeed or fail remain to be clarified.Objectives: We investigated the accuracy of existing LSSs both theoretically and numerically by Monte Carlo simulation. We also proposed two new methods for more accurate AUC estimations.Methods: We evaluated the following existing methods theoretically: i) nonlinear curve fitting algorithm (NLF), ii) the trapezium rule with exponential curve approximation (TZE), and iii) multiple linear regression (MLR). Taking busulfan (BU) as a test drug, we generated a set of theoretical concentration-time curves based on the identified distribution of pharmacokinetic parameters of BU and re-evaluated the existing LSSs using these virtual validation profiles. Based on the evaluation results, we improved the TZE so that unrealistic parameter values were not used. We also proposed a new estimation method in which the most likely curve was selected from a set of pre-generated theoretical concentration-time curves.Results: Our evaluation, based on clinical profiles and a virtual validation set, revealed: i) NLF sometimes overestimated the absorption rate constant Ka, ii) TZE overestimated AUC over 280% when Ka is small, and iii) MLR underestimated AUC over 30% when the elimination rate constant Ke is small. These results were consistent with our mathematical evaluations for these methods. In contrast, our two new methods had little bias and good precision.Conclusions: Our investigation revealed that existing LSSs induce different but specific biases in the estimation of AUC. Our two new LSSs, a modified TZE and one using model concentration-time curves, provided accurate and precise estimations of AUC.

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PHARMACODYNAMICS EFFECT OF METHYLPREDNISOLONE TABLETS ON THE SERUM CONCENTRATION OF ANNEXIN A1: IN VIVO COMPARATIVE STUDY BETWEEN GENERIC AND INNOVATOR DRUG

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2019.v12i1.30010 ◽

2019 ◽

Vol 12 (1) ◽

pp. 414

Author(s):

Hansen Nasif ◽

Henny Lucida ◽

Yanwirasti Yanwirasti ◽

Yufri Aldi ◽

Yori Yuliandra

Keyword(s):

Serum Concentration ◽

Peak Concentration ◽

Peak Time ◽

Annexin A1 ◽

Onset Of Action ◽

Time Curve ◽

Concentration Time ◽

Significant Difference ◽

Generic Products

Objective: The aims of this study were to investigate the comparative pharmacodynamics effect of methylprednisolone (MP) innovator, MP branded generic, and MP generic products to the serum concentration of annexin A1 (AnxA1).Methods: It was conducted by two-way crossover design in male rabbits. AnxA1 was measured at 0, 0.5, 1, 2, 3, 5, 7, and 9 h after the administration of the drugs. The peak concentration (Cmax), the time at which the peak concentration was achieved (Tmax), and the area under the plasma concentration-time curve (AUC) were also determined.Results: The highest concentration and widest AUC of AnxA1 were obtained in MP innovator drug. MP innovator and branded generic reaches the peak time (Tmax) at the third 3rd h, while the MP generic reaches the peak time at the 5th h. The results showed that there was no significant difference in the serum concentration of AnxA1 between MP tablets after analyzed with a one-way analysis of variance.Conclusion: It could be concluded that the innovator drug of MP tablet gave the same effect on the serum concentration of AnxA1 than its generic counterparts, but an onset of action MP innovator and branded generic is faster than the generic product.

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Domestic Cat Model for Predicting Human Nucleoside Analogue Pharmacokinetics in Blood and Seminal Plasma

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.7.2173-2176.2001 ◽

2001 ◽

Vol 45 (7) ◽

pp. 2173-2176 ◽

Cited By ~ 4

Author(s):

Holly L. Jordan ◽

Arlene S. Pereira ◽

Myron S. Cohen ◽

Angela D. M. Kashuba

Keyword(s):

Seminal Plasma ◽

Nucleoside Analogue ◽

Domestic Cat ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Concentration Time ◽

Feline Model ◽

Cat Model ◽

Male Genital

ABSTRACT To establish whether a feline model can predict nucleoside analogue behavior in human semen, zidovudine (ZDV) and lamivudine (3TC) pharmacokinetic parameters (PKs) were determined in the blood and seminal plasma of healthy cats. Our results show considerable similarity in ZDV and 3TC PKs between cats and humans. As in humans, ZDV and 3TC tend to accumulate in feline seminal plasma. Area under the blood plasma concentration-time curve was predictive of seminal plasma excretion. The felid model offers a unique in vivo experimental alternative for investigating the pharmacokinetics of nucleoside analogues in the male genital tract.

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Comparative Assessment of Tedizolid Pharmacokinetics and Tissue Penetration between Diabetic Patients with Wound Infections and Healthy Volunteers via In Vivo Microdialysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01880-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 3

Author(s):

Sean M. Stainton ◽

Marguerite L. Monogue ◽

Arlinda Baummer-Carr ◽

Ashley K. Shepard ◽

James F. Nugent ◽

...

Keyword(s):

Healthy Volunteers ◽

Subcutaneous Tissue ◽

Extracellular Fluid ◽

Pharmacokinetic Parameters ◽

Diabetic Patients ◽

Tissue Penetration ◽

Time Curve ◽

Dosing Interval ◽

Concentration Time

ABSTRACT Herein, we present pharmacokinetic and tissue penetration data for oral tedizolid in hospitalized patients with diabetic foot infections (DFI) compared with healthy volunteers. Participants received oral tedizolid phosphate 200 mg every 24 h for 3 doses to achieve steady state. A microdialysis catheter was inserted into the subcutaneous tissue near the margin of the wound for patients or into thigh tissue of volunteers. Following the third dose, 12 blood and 14 dialysate fluid samples were collected over 24 h to characterize tedizolid concentrations in plasma and interstitial extracellular fluid of soft tissue. Mean ± standard deviation (SD) tedizolid pharmacokinetic parameters in plasma for patients compared with volunteers, respectively, were as follows: maximum concentration (C max), 1.5 ± 0.5 versus 2.7 ± 1.1 mg/liter (P = 0.005); time to C max (T max) (median [range]), 5.9 (1.2 to 8.0) versus 2.5 (2.0 to 3.0 h) (P = 0.003); half-life (t1/2), 9.1 ± 3.6 versus 8.9 ± 2.2 h (P = 0.932); and plasma area under the concentration-time curve for the dosing interval (AUC p ), 18.5 ± 9.7 versus 28.7 ± 9.6 mg · h/liter (P = 0.004). The tissue area under the concentration-time curve (AUC t ) for the dosing interval was 3.4 ± 1.5 versus 5.2 ± 1.6 mg · h/liter (P = 0.075). Tissue penetration median (range) was 1.1 (0.3 to 1.6) versus 0.8 (0.7 to 1.0) (P = 0.351). Despite lower plasma C max and delayed T max values for patients with DFI relative to healthy volunteers, the penetration into and exposure to tissue were similar. Based on available pharmacodynamic thresholds for tedizolid, the plasma and tissue exposures using the oral 200 mg once-daily regimen are suitable for further study in treatment of DFI.

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Pharmacokinetics of Florfenicol in Healthy Pigs and in Pigs Experimentally Infected with Actinobacillus pleuropneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.2.820-823.2003 ◽

2003 ◽

Vol 47 (2) ◽

pp. 820-823 ◽

Cited By ~ 52

Author(s):

Jianzhong Liu ◽

Ki-Fai Fung ◽

Zhangliu Chen ◽

Zhenling Zeng ◽

Jie Zhang

Keyword(s):

Half Life ◽

Clinical Signs ◽

Actinobacillus Pleuropneumoniae ◽

Pharmacokinetic Parameters ◽

X Rays ◽

Time Data ◽

Time Curve ◽

Chromatography Method ◽

Concentration Time ◽

Significant Difference

ABSTRACT A comparative in vivo pharmacokinetic study of florfenicol was conducted in 18 crossbred pigs infected with Actinobacillus pleuropneumoniae following intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration of a single dose of 20 mg/kg. The disease model was confirmed by clinical signs, X rays, pathohistologic examinations, and organism isolation. Florfenicol concentrations in plasma were determined by a validated high-performance liquid chromatography method with UV detection at a wavelength of 223 nm. Pharmacokinetic parameters were calculated by using the MCPKP software (Research Institute of Traditional Chinese Veterinary Medicine, Lanzhou, China). The disposition of florfenicol after a single i.v. bolus was described by a two-compartment model with values for the half-life at α phase (t 1/2α), the half-life at β phase (t 1/2β), the area under the concentration-time curve (AUC0-∞), and the volume of distribution at steady state (V ss) of 0.37 h, 2.91 h, 64.86 μg · h/ml, and 1.2 liter/kg, respectively. The concentration-time data fitted the one-compartment (after i.m.) and two-compartment (after p.o.) models with first-order absorption. The values for the maximum concentration of drug in serum (C max), t 1/2α, t 1/2β, and bioavailability after i.m. and p.o. dosing were 4.00 and 8.11 μg/ml, 0.12 and 3.91 h, 13.88 and 16.53 h, and 122.7 and 112.9%, respectively, for the two models. The study showed that florfenicol was absorbed quickly and completely, distributed widely, and eliminated slowly in the infected pigs, and there was no statistically significant difference between the pharmacokinetic profiles for the infected and healthy pigs.

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Pharmacokinetics of Azithromycin Administered Alone and with Atovaquone in Human Immunodeficiency Virus-Infected Children

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.6.1516 ◽

1999 ◽

Vol 43 (6) ◽

pp. 1516-1519 ◽

Cited By ~ 5

Author(s):

Leock Y. Ngo ◽

Ram Yogev ◽

Wayne M. Dankner ◽

Walter T. Hughes ◽

Sandra Burchett ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Steady State ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Concentration Time ◽

Significant Difference ◽

Immunodeficiency Virus ◽

The Mean ◽

Clinically Significant ◽

To Receive

ABSTRACT To evaluate if atovaquone (ATQ) interacts pharmacokinetically with azithromycin (AZ) in human immunodeficiency virus-infected children, 10 subjects (ages, 4 to 13 years) were randomized in a crossover study to receive AZ (5 mg/kg/day) alone (ALONE) or AZ (5 mg/kg/day) and ATQ (30 mg/kg/day) simultaneously (SIM) prior to receiving AZ and ATQ staggered by 12 h. Despite a lack of significant difference in the mean AZ pharmacokinetic parameters, the steady-state values of AZ’s area under the concentration-time curve from 0 to 24 h and maximum concentration in serum were consistently lower (n = 7 of 7) for the SIM regimen than they were for the ALONE regimen. A larger study will be required to determine if ATQ affects AZ pharmacokinetics and efficacy in a clinically significant manner.

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A Rapid and Sensitive UHPLC-MS/MS Method for Determination of 2, 3, 8-Trimethylellagic, a Potent Active Compound from Sanguisorba officinalis L., and Its Application in the Pharmacokinetic Study within Thrombocytopenia Rats

Journal of Chemistry ◽

10.1155/2021/3309434 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Yuqing Wang ◽

Jianming Wu ◽

Yunxia Li ◽

Jing Yang ◽

Long Wang ◽

...

Keyword(s):

Plasma Concentration ◽

Maximum Concentration ◽

High Performance ◽

Internal Standard ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Concentration Time ◽

Relative Standard ◽

Plasma Concentration Time Curve

To investigate the pharmacokinetics of 2, 3, 8-trimethylellagic (TMEA) in rats in vivo and determine the possible effects of the pathological conditions and compatibility, a rapid and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for quantitative determination was developed. TMEA and Artemetin (internal standard, IS) were separated on an Acquity Shim-pack GIST column with a total running time of 7 min using gradient elution at a flow rate of 0.3 mL/min. The intraday and interday relative standard deviations were <9.50%, and the relative error of accuracy was between −5.70% and 2.96%. The calibration curve of TMEA demonstrated good linearity with r2 = 0.9996, with the average recovery changing from 94.77% to 102.47% and the matrix effect from 93.16% to 100.15%. Compared with the normal group, the area under the plasma concentration-time curve from time 0 to the last time of quantifiable concentration (AUC(0 − t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0 − ∞)), and the maximum concentration (Cmax) of TMEA increased, whereas the time of maximum concentration (Tmax) and apparent clearance (CL/F) remarkably decreased in the TMEA group. With significantly reduced CL/F, AUC(0 − t), AUC(0 − ∞), and Cmax for TMEA were increased approximately one time after combining with 3, 7-Di-O-methylducheside A (DOMA). AUC(0 − t) and Cmax for TMEA in the 2, 3, 8-trimethylellagic-3, 8-dimethoxyellagic acid-2-oxyglucoside (TMEA-DMAG) group were significantly lower than that in the TMEA group with clearly prolonged Tmax and increased CL/F. These findings indicate that the changes in the pharmacokinetic parameters of TMEA may be caused by pathological and combination conditions.

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Altered Pharmacokinetics of Daunorubicin in Rats with CCl4-Induced Hepatic Injury

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3mw28 ◽

2007 ◽

Vol 10 (4) ◽

pp. 443 ◽

Cited By ~ 3

Author(s):

Min-Koo Choi ◽

Im-Sook Song ◽

Dae-Duk Kim ◽

Suk-Jae Chung ◽

Chang-Koo Shim

Keyword(s):

Hepatic Injury ◽

Hepatic Metabolism ◽

Isolated Hepatocytes ◽

Fasting Period ◽

Time Curve ◽

Concentration Time ◽

Single Intraperitoneal Injection ◽

In Vivo Pharmacokinetics

PURPOSE. The effect of CCl4-induced experimental hepatic injury (CCl4-EHI) on the pharmacokinetics of daunorubicin was investigated systemically in rats, in an attempt to elucidate the major determinants of the effect of CCl4-EHI on the pharmacokinetics of the drug. METHODS. CCl4-EHI was induced in rats by a single intraperitoneal injection of CCl4 (1mL/kg rat), and a 24 h fasting period. Daunorubicin was administered intravenously to control and EHI rats at a dose of 11.3 mg/mL/kg and the in vivo pharmacokinetics was studied. The in vitro uptake of the drug into isolated hepatocytes and canalicular liver plasma membrane (cLPM) vesicles, as well as the liver microsomal degradation of the drug, were also determined. RESULTS. The area under the plasma concentration-time curve (AUC) of daunorubicin was increased by 1.6 times, resulting in a 34% decrease in the systemic clearance (CL) in rats with CCl4-EHI. The apparent biliary (CLbile) and urinary (CLurine) clearance of the drug were unchanged, whereas the AUC of daunorubicinol, the major metabolite of daunorubicin, was decreased by 66% in rats with CCl4-EHI. EHI seemed to affect the hepatobiliary elimination of the drug in several ways: the in vitro intrinsic sinusoidal uptake clearance was decreased by 20%; the in vitro intrinsic canalicular excretion clearance of the drug was increased by 1.7 times; and the in vitro liver microsomal degradation of daunorubicin was significantly retarded. CONCLUSIONS. CCl4-EHI appears to impair the hepatic metabolism of daunorubicin, thereby decreasing the CL and increasing the AUC of daunorubicin.

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