Critical evaluation of the potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve

1978 ◽  
Vol 6 (6) ◽  
pp. 539-546 ◽  
Author(s):  
Win L. Chiou
Keyword(s):  
Plasma Level ◽  
Critical Evaluation ◽  
Trapezoidal Rule ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Potential Error ◽  
Linear Trapezoidal Rule ◽  
Rule Method

scholarly journals Rational application of fructose-1,6-diphosphate: From the perspective of pharmacokinetics

2015 ◽  
Vol 65 (2) ◽  
pp. 147-157 ◽  
Author(s):  
Ting-Ting Li ◽  
Jian-Zhong Xie ◽  
Ling Wang ◽  
Yang-Yang Gao ◽  
Xue-Hua Jiang
Keyword(s):  
Plasma Level ◽  
Intestinal Epithelium ◽  
High Dose ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Human Data ◽  
Multiple Doses ◽  
Epithelium Cells ◽  
Monolayer Model

Abstract Fructose-1,6-diphosphate (FDP), a glycolytic metabolite, has been reported to protect susceptible organs during hypoxia or ischemia. However, there is paucity of human data on its pharmacokinetics after being exogenously administered. In the current study, the preliminary pharmacokinetics of FDP given orally to humans was investigated, and no typical peak was observed in the serum drug-time curve. Then, the pharmacokinetic studies were performed following multiple doses of FDP in rats, and the Caco-2 monolayer model was used to study the absorption of FDP in vitro. The results suggested that plasma FDP concentration was significantly increased after oral multiple doses of 180 mg kg-1 but not 90 mg kg-1 of FDP, and FDP was partly depleted during the absorption, which was supposed to be consumed by the intestinal epithelium cells. Thus, we conclude that a high dose of FDP should be orally administered in order to get an effective plasma level.

scholarly journals Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability and Favorable Pharmacokinetic Profile in Preclinical ADME Studies

2021 ◽  
Vol 14 (8) ◽  
pp. 719
Author(s):  
Jiawang Liu ◽  
Nirmal Rajasekaran ◽  
Ahamed Hossain ◽  
Changde Zhang ◽  
Shanchun Guo ◽  
...  
Keyword(s):  
Boronic Acid ◽  
Oral Bioavailability ◽  
Drug Exposure ◽  
Liver Microsomes ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Studies ◽  
Dependent Manner ◽  
Mucosal Permeability ◽  
Time Curve ◽  
Concentration Dependent Manner

Fulvestrant-3-boronic acid (ZB716), an oral selective estrogen receptor degrader (SERD) under clinical development, has been investigated in ADME studies to characterize its absorption, metabolism, and pharmacokinetics. ZB716 was found to have high plasma protein binding in human and animal plasma, and low intestinal mucosal permeability. ZB716 had high clearance in hepatocytes of all species tested. ZB716 was metabolized primarily by CYP2D6 and CYP3A. In human liver microsomes, ZB716 demonstrated relatively low inhibition of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 (when testosterone was used as the substrate), and no inhibition of CYP2B6 and 3A4 (when midazolam was used as the substrate). In assays for enzyme activity, ZB716 induced CYP1A2, 2B6, and 3A4 in a concentration-dependent manner. Single-dose and repeated-dose pharmacokinetic studies in rats and dogs showed oral bioavailability, dose-proportional drug exposure, and drug accumulation as measured by maximum concentration and area under the concentration–time curve (AUC).

scholarly journals Drug Interactions Between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine

2018 ◽  
Author(s):  
Stephen I Walimbwa ◽  
Mohammed Lamorde ◽  
Catriona Waitt ◽  
Julian Kaboggoza ◽  
Laura Else ◽  
...  
Keyword(s):  
Maximum Concentration ◽  
Geometric Mean ◽  
Compartmental Analysis ◽  
Sub Saharan Africa ◽  
Pharmacokinetic Studies ◽  
Serious Adverse Events ◽  
Time Curve ◽  
Once Daily ◽  
Trough Concentrations ◽  
Sub Saharan

ABSTRACTAcross sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether-lumefantrine or artesunate-amodiaquine and DTG. The DTG/artmether-lumefantrine interaction was evaluated in a two-way cross-over study and measured artemether (ARM), dihydroartemisinin (DHA), lumefantrine (LF), desbutyl-lumefantrine (DBL) over 264h. The DTG/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine (DEAQ) and measured artesunate (ARS), amodiaquine (AQ), DEAQ over 624h. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, time to maximum concentration and area under the concentration-time curve (AUC) for ARM, DHA, LF and DBL nor significantly alter AUC for ARS, DHA, AQ and DEAQ. Co-administration of dolutegravir with AL resulted in a 37% decrease in DTG trough concentrations. Co-administration of dolutegravir with AS-AQ resulted in a decrease of approximately 42% and 24% in DTG trough concentrations and AUC respectively. Study drugs were well-tolerated with no serious adverse events. Standard doses of artmether-lumefantrine and artesunate-amodiaquine should be used in patients receiving DTG. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and DTG exposure with artesunate-amodiaquine are unlikely to be of clinical significance as DTG trough concentrations were above DTG target concentrations of 64ng/mL.

scholarly journals Pharmacokinetic studies of 1.ALPHA.,24(R)-(OH)2D3(TV-02)(5). Plasma level and excretion in beagle dogs.

1990 ◽  
Vol 5 (1) ◽  
pp. 63-69
Author(s):  
Tomohiro OHTA ◽  
Hirohide MIMURA ◽  
Masaru YAMAMOTO ◽  
Mamoru KIYOKI ◽  
Takeo OHBA ◽  
...  
Keyword(s):  
Plasma Level ◽  
Pharmacokinetic Studies ◽  
Beagle Dogs

scholarly journals Pharmacokinetic studies of 1.ALPHA., 24(R)-(OH)2D3(TV-02)(2). Plasma level, distribution, metabolism and excretion after repeated subcutaneous administration to rats.

1990 ◽  
Vol 5 (1) ◽  
pp. 25-37 ◽  
Author(s):  
Tomohiro OHTA ◽  
Masaru YAMAMOTO ◽  
Hirohide MIMURA ◽  
Takashi MATSUNAGA ◽  
Mamoru KIYOKI ◽  
...  
Keyword(s):  
Plasma Level ◽  
Subcutaneous Administration ◽  
Pharmacokinetic Studies

scholarly journals In Vivo Pharmacodynamic Characterization of a Novel Odilorhabdin Antibiotic, NOSO-502, against Escherichia coli and Klebsiella pneumoniae in a Murine Thigh Infection Model

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Miao Zhao ◽  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
David R. Andes
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Subcutaneous Administration ◽  
Dose Fractionation ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Content Type ◽  
The Mean

ABSTRACT NOSO-502 is a novel odilorhabdin antibiotic with potent activity against Enterobacteriaceae. The goal of these studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitude best correlated with efficacy in the murine thigh infection model. Six Escherichia coli and 6 Klebsiella pneumoniae isolates were utilized. MICs were determined using CLSI methods and ranged from 1 to 4 mg/liter. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after subcutaneous administration of 7.81, 31.25, 125, and 500 mg/kg of body weight. Pharmacokinetic studies exhibited peak concentration (Cmax) values of 1.49 to 84.6 mg/liter, area under the concentration-time curve from 0 h to infinity (AUC0–∞) values of 1.94 to 352 mg · h/liter, and beta elimination half-lives of 0.41 to 1.1 h. Dose fractionation studies were performed using total drug doses of 7.81 mg/kg to 2,000 mg/kg fractionated into regimens of every 3 h (q3h), q6h, q12h, or q24h. Nonlinear regression analysis demonstrated that AUC/MIC was the PK/PD parameter that best correlated with efficacy (R2, 0.86). In subsequent studies, we used the neutropenic murine thigh infection model to determine the magnitude of NOSO-502 AUC/MIC needed for the efficacy against a diverse group of Enterobacteriaceae. Mice were treated with 4-fold-increasing doses (range, 3.91 to 1,000 mg/kg) of NOSO-502 every 6 h. The mean 24-h free-drug AUC/MIC (fAUC)/MIC) magnitudes associated with net stasis and 1-log kill endpoint for K. pneumoniae were 4.22 and 17.7, respectively. The mean fAUC/MIC magnitude associated with net stasis endpoint for E. coli was 10.4. NOSO-502 represents a promising novel, first-in-class odilorhabdin antibiotic with in vivo potency against Enterobacteriaceae.

scholarly journals Percutaneous Microdialysis and Pharmacokinetic Study of Tongluo-Qutong Rubber Plaster in Rats by UPLC-MS/MS

2020 ◽  
Vol 15 (9) ◽  
pp. 1934578X2095782
Author(s):  
Jiaxin Pi ◽  
Ying Zhang ◽  
Xutong Ma ◽  
Ping Wang ◽  
Wei Xiong ◽  
...  
Keyword(s):  
Pharmacokinetic Study ◽  
Pharmacokinetic Studies ◽  
Active Ingredients ◽  
Time Curve ◽  
Liquid Chromatography Tandem Mass ◽  
Medicine Prescription ◽  
The Mean ◽  
Microdialysis Study ◽  
Dermal Administration

Tongluo-Qutong rubber plaster (TQRP) is a well-known traditional Chinese medicine prescription for the treatment of osteoarthritis and cervical spondylosis. Due to a lack of in vivo permeation data, the active ingredients of TQRP have not been fully elucidated, presenting a huge obstacle to quality evaluation, pharmacokinetic studies, and safety assessment of TQRP for clinical application. In this study, a selective and reproducible ultraperformance liquid chromatography tandem mass spectrometry method was developed and validated for percutaneous microdialysis and pharmacokinetic experiments. In the percutaneous microdialysis study, the mean area under the concentration–time curve (AUC0-24h) of emodin (EMO) and piperine (PIP) were 127.1 and 2603.6 h·ng/mL, respectively. In the pharmacokinetic study, ferulic acid (FA), EMO, and PIP were determined in plasma samples. The mean AUC0-32h values of FA, EMO, and PIP in plasma were 15441.5, 202.0, and 1704.5 h·ng/mL, respectively. The in vivo exposure levels of active ingredients such as FA, EMO, and PIP after dermal administration of TQRP provide insights and data to support identification of its bioactive components and further study of its mechanism of action.

In Vivo Inhibition Of Thromboxane A2-Synthetase : Protective Effect Against Collagen And Arachidonate Infusion

1981 ◽  
Author(s):  
D Sincholle ◽  
C Fontaine ◽  
B Martin ◽  
C Bonne ◽  
P Regnault
Keyword(s):  
Blood Pressure ◽  
Plasma Level ◽  
Oral Treatment ◽  
Lethal Dose ◽  
Thromboxane A2 ◽  
Pharmacokinetic Studies ◽  
Antithrombotic Drugs ◽  
Thromboxane Synthetase ◽  
Derivatives Of

Rabbits and rats anaesthetised with thiopental were infused intravenously either with sodium arachidonate or collagen. Blood pressure and pneumogram were recorded and Thromboxane B2 (T×B2) plasma level was measured prior and after infusion. The aggregating agents elicited hypotension, respiratory break down and killed the animals. These events were associated with an increase in plasma T×B2 concentration. Intraperitoneal pretreatment of animals with derivatives of imidazole (1 -(3-hydroxy-1-oct enyl)-imidazole , chlorhydrat e (CBS6l2) and its nicotinic ester (CBS634) delayed toxic effects and death. In the standard conditions used in this study, the lethal dose of arachidonate in the rabbit was 8.4 t 1.0 mg/kg. This dose was increased to 21.6 ± 4.3 and 50.4 ± 8.0 when the animals were pretreated with CBS6l2 at the dose of respectively 12.5 mg/kg and 25 mg/kg. In the same way, the lethal dose of collagen in the rat was 0.5 ± 0.1 mg/kg in controls and 1.2 t 0.1 mg/kg after treatment with thromboxane-synthetase inhibitor (CBS634 = 25 mg/kg). The lethal dose of collagen was correlated to the concentration of T×B2 formed in the blood (controls : 4.4 ± 0.3 ; treated : 1.7 ± 0.2 ng/ml).Potential interest of these antithrombotic drugs could be strengthened by further pharmacokinetic studies after oral treatment actually in progress.

scholarly journals Differential Effects of 1α,25-Dihydroxyvitamin D3 on the Expressions and Functions of Hepatic CYP and UGT Enzymes and Its Pharmacokinetic Consequences In Vivo

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1129
Author(s):  
Trang Nguyen Kieu Doan ◽  
Dang-Khoa Vo ◽  
Hyojung Kim ◽  
Anusha Balla ◽  
Yunjong Lee ◽  
...  
Keyword(s):  
Active Form ◽  
Liver Microsomes ◽  
Pharmacokinetic Studies ◽  
Uridine Diphosphate ◽  
Time Curve ◽  
Dihydroxyvitamin D3 ◽  
Additional Information ◽  
Protein Expressions

The compound 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) is the active form of vitamin D3 and a representative ligand of the vitamin D receptor (VDR). Previous studies have described the impacts of 1,25(OH)2D3 on a small number of cytochrome P450 (CYP) and uridine diphosphate-glucuronyltransferase (UGT) enzymes, but comparatively little is known about interactions between several important CYP and UGT isoforms and 1,25(OH)2D3 in vitro and/or in vivo. Thus, we investigated the effects of 1,25(OH)2D3 on the gene and protein expressions and functional activities of selected CYPs and UGTs and their impacts on drug pharmacokinetics in rats. The mRNA/protein expressions of Cyp2b1 and Cyp2c11 were downregulated in rat liver by 1,25(OH)2D3. Consistently, the in vitro metabolic kinetics (Vmax and CLint) of BUP (bupropion; a Cyp2b1 substrate) and TOL (tolbutamide; a Cyp2c11 substrate) were significantly changed by 1,25(OH)2D3 treatment in liver microsomes, but the kinetics of acetaminophen (an Ugt1a6/1a7/1a8 substrate) remained unaffected, consistent with Western blotting data for Ugt1a6. In rat pharmacokinetic studies, the total body clearance (CL) and nonrenal clearance (CLNR) of BUP were significantly reduced by 1,25(OH)2D3, but unexpectedly, the total area under the plasma concentration versus time curve from time zero to infinity (AUC) of hydroxybupropion (HBUP) was increased probably due to a marked reduction in the renal clearance (CLR) of HBUP. Additionally, the AUC, CL, and CLNR for TOL and the AUC for 4-hydroxytolbutamide (HTOL) were unaffected by 1,25(OH)2D3 in vivo. Discrepancies between observed in vitro metabolic activity and in vivo pharmacokinetics of TOL were possibly due to a greater apparent distribution volume at the steady-state (Vss) and lower plasma protein binding in 1,25(OH)2D3-treated rats. Our results suggest possible drug-drug and drug-nutrient interactions and provide additional information concerning safe drug combinations and dosing regimens for patients taking VDR ligand drugs including 1,25(OH)2D3.

scholarly journals Pharmacokinetics of Nelfinavir and Efavirenz in Antiretroviral-Naïve, Human Immunodeficiency Virus-Infected Subjects when Administered Alone or in Combination with Nucleoside Analog Reverse Transcriptase Inhibitors

2005 ◽  
Vol 49 (8) ◽  
pp. 3558-3561 ◽  
Author(s):  
Patrick F. Smith ◽  
Gregory K. Robbins ◽  
Robert W. Shafer ◽  
Hulin Wu ◽  
Song Yu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Half Life ◽  
Pharmacokinetic Studies ◽  
Reverse Transcriptase Inhibitors ◽  
Time Curve ◽  
Minimum Concentration ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
The Mean

ABSTRACT Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.

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