Residual fraction of the area under the curve as a qualitative criterion in pharmacokinetic studies

Periploca forrestii Schltr ( P. forrestii) is a herb used in traditional Chinese medicine for its anti-rheumatoid arthritis effect. The aim of this study was to compare the pharmacokinetic properties of the 5 active components of this plant: neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, isochlorogenic acid C, and periplocin between normal rats and adjuvant-induced arthritis model rats. After the intravenous administration (177.78 mg/kg) of P. forrestii extract, samples were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry. Compared with normal rats, the area under the curve [(AUC)(0-t), AUC(0-∞)], mean residence time [(MRT)(0-t), MRT(0-∞)] of neochlorogenic acid-treated rats decreased significantly, and drug clearance (CL) and apparent volume of distribution (V) increased significantly; the V of chlorogenic acid-treated rats decreased significantly, and MRT(0-t) significantly increased; the AUC(0-t) and AUC(0-∞) of cryptochlorogenic acid-treated rats decreased significantly, and CL and V increased significantly; the AUC(0-t) and MRT(0-t) of isochlorogenic acid C-treated rats decreased significantly, and V increased significantly; the AUC(0-t) and AUC(0-∞) of periplocin-treated rats increased significantly, and MRT(0-t), MRT(0-∞), CL, and V decreased significantly in model rats. The disease condition of rheumatoid arthritis in rats had a significant effect on the in vivo pharmacokinetics of P. forrestii after the intravenous administration.

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PHARMACOKINETIC STUDIES OF A CHRONOTHERAPEUTIC DRUG DELIVERY SYSTEM OF LORNOXICAM BY LC-MS/MS METHOD

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2018v10i6.27453 ◽

2018 ◽

Vol 10 (6) ◽

pp. 88

Author(s):

Sindhu Abraham ◽

Rajamanickam Deveswaran ◽

Jayaraman Anbu ◽

Sharon Furtado ◽

Bharath Srinivasan

Keyword(s):

Drug Delivery ◽

Drug Release ◽

Maximum Concentration ◽

Area Under The Curve ◽

Immediate Release ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Studies ◽

Elimination Half ◽

Coated Tablet ◽

Liquid Chromatography Tandem Mass

Objective: The objective of this study was to investigate differences in pharmacokinetic patterns of immediate release tablet (IR) and compression coated tablet (CCT) of lornoxicam, proposed for the chronotherapeutic treatment of rheumatoid arthritis.Methods: The dosage forms were administered to two groups of white New Zealand rabbits (n=3), and the plasma drug levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters like maximum concentration (Cmax), time is taken to reach maximum concentration (Tmax), area under the curve (AUC), elimination half-life (t1/2) and Mean Residence Time (MRT) were determined.Results: In the case of IR tablets, the drug was detected within 15 min after oral administration and a Cmax of 1269.57±4.04 ng/ml were attained at 2±0.15 h. With CCT, the drug was detected only after 5 h and a Cmax of 1279.24±12.76 ng/ml were attained at 8±0.10 h. The CCT showed maximum drug release at the eighth hour in comparison to IR tablet which showed maximum release at the second hour of study.Conclusion: The predominant lag time prior to drug release from CCT is an indication that it is consistent with the requirements of chronopharmaceutical drug delivery. The results suggest that the compression coated tablet is a promising approach for chronotherapeutic management of rheumatoid arthritis.

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Pharmacokinetics of L-arginine during chronic administration to patients with hypercholesterolaemia

Clinical Science ◽

10.1042/cs0960199 ◽

1999 ◽

Vol 96 (2) ◽

pp. 199-207 ◽

Cited By ~ 13

Author(s):

Oranee TANGPHAO ◽

Stephan CHALON ◽

Heitor MORENO ◽

Brian B. HOFFMAN ◽

Terrence F. BLASCHKE

Keyword(s):

Nitric Oxide ◽

Animal Studies ◽

Peak Plasma ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Chronic Administration ◽

Pharmacokinetic Studies ◽

Acute Administration ◽

Term Administration ◽

Endothelial Nitric Oxide

Acute administration of L-arginine, the precursor of endothelial nitric oxide, has been shown to improve endothelial function in hypercholesterolaemic rabbits and humans. Animal studies suggest that this beneficial effect, which is thought to be related to the increased availability of nitric oxide, may not be sustained during chronic oral administration. Pharmacokinetic alterations may contribute to this observation. The present study was designed to examine the disposition of L-arginine in hypercholesterolaemic subjects during long-term administration. Plasma L-arginine concentrations were determined by HPLC in 10 patients (eight women and two men; mean age 46±16 years) after an intravenous dose of 10 or 30 g and an oral dose of 5 or 7 g. Pharmacokinetic studies were performed at regular intervals (4 weeks) during a 12-week period of oral L-arginine administration (14–21 g/day). The average plasma L-arginine concentrations before (baseline) and during administration were 16.1±1.2 and 22.5±1.3 μg/ml respectively (P< 0.05). Plasma concentrations of L-arginine remained above baseline throughout weeks 2–12. The L-arginine exposure, expressed as a normalized area-under-the-curve for 8 h (AUC0–8) after oral or intravenous doses during the first visit, was 894.4±118.7 and 1837.8±157.0 units respectively. There were no significant changes in peak plasma L-arginine concentrations or in the AUC0–8 after oral and intravenous doses during subsequent visits (P> 0.05). The mean non-renal clearance of L-arginine during the four visits remained constant. Knowledge of the pharmacokinetics of L-arginine may be useful in the design of clinical trials involving this agent, as well as in the interpretation of the pharmacodynamics of this important precursor of nitric oxide.

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Clinical Pharmacokinetics of Enalapril and Enalaprilat in Pediatric Patients—A Systematic Review

Frontiers in Pediatrics ◽

10.3389/fped.2021.611322 ◽

2021 ◽

Vol 9 ◽

Author(s):

Muhammad Faisal ◽

Willi Cawello ◽

Stephanie Laeer ◽

Keyword(s):

Heart Failure ◽

Active Metabolite ◽

Pediatric Patients ◽

Age Groups ◽

Area Under The Curve ◽

Pharmacokinetic Studies ◽

Hypertensive Patients ◽

Patients With Heart Failure ◽

Pediatric Heart Failure ◽

Enalapril And Enalaprilat

Purpose: Enalapril has an established safety and efficacy in adults and is used in hypertension, heart failure, and renal failure. In pediatric patients, enalapril is labeled for children with hypertension and used off label in children with heart failure. The systematic literature search aims to assess the current knowledge about enalapril and its active metabolite enalaprilat pharmacokinetics in children as a basis for dose delineation for pediatric patients with heart failure.Methods: A systematic literature review was performed in the PubMed database using relevant keywords. Dose normalization of relevant pharmacokinetic parameters of the identified studies was done for comparison between different diseases and pediatric age groups.Results: The literature search has resulted in three pediatric pharmacokinetic studies of enalapril out of which Wells et al. reported about children with hypertension and Nakamura et al., and Llyod et al. presented data for pediatric heart failure patients. The area under the curve values of enalaprilat in hypertensive pediatric patients increased with respect to the age groups and showed maturation of body functions with increasing age. Dose normalized comparison with the heart failure studies revealed that although the pediatric heart failure patients of > 20 days of age showed the area under the curve a similar to that of hypertensive patients, two pediatric patients of very early age (<20 days) were presented with 5–6-fold higher area under the curve values.Conclusion: Data related to the pharmacokinetics of enalapril and enalaprilat in hypertensive patients and few data for young heart failure children are available. Comparison of dose normalized exposition of the active metabolite enalaprilat indicated similarities between heart failure and hypertensive patients and a potentially high exposition of premature patients but substantially more pharmacokinetic studies are required to have reliable and robust enalapril as well as enalaprilat exposures especially in pediatric patients with heart failure as a basis for any dose delineation.

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1119. Assessment of Vancomycin Pharmacokinetic Parameters in Pediatric Patients After Liver Transplantation

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1312 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S651-S652

Author(s):

Ronaldo Morales ◽

Vanessa D Juodinis ◽

Daniela Carla de Souza ◽

Silvia Regina C Jorge Santos

Keyword(s):

Liver Transplantation ◽

Therapeutic Target ◽

Bacterial Infections ◽

Pediatric Patients ◽

Area Under The Curve ◽

Compartment Model ◽

Volume Of Distribution ◽

Critical Conditions ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Studies

Abstract Background Vancomycin is largely prescribed to treat gram-positive bacterial infections in pediatric patients after liver transplantation with the same empirical doses prescribed in other critical conditions due to the absence of pharmacokinetic studies in this population. The objective of this investigation was to describe the vancomycin pharmacokinetic parameters and to assess the vancomycin percentage of target attainment with empirical regimen. Methods Prospective and longitudinal study with pediatric post-liver transplantation patients who received at least 48 hours of vancomycin between January 2020 and May 2021. Patients with acute or chronic renal failure or receiving renal replacement therapy were excluded. Vancomycin therapy started with 40-60mg/kg daily, one-hour infusion. The pharmacokinetic parameters were determined by one-compartment model with first-order kinetics using near steady-state postdistributional peak and trough within the same dosing interval. Therapeutic target was defined as vancomycin 24-hour area under the curve/minimum inhibitory concentration (AUCss0-24/MIC) ≥ 400 and < 600. The study protocol was approved by the local ethics committee. Results We included 18 sets of peak/trough serum concentrations obtained from 12 patients. The patients had median age of 11 (interquartile range [IQ] 8-16) months. The found vancomycin clearance, volume of distribution and half-life values were, respectively, 2.1 (IQ 1.4-2.8) mL/kg/min, 0.6 (IQ 0.5-0.7) L/kg and 3.2 (IQ 2.3-4.0) hours. After the initial dose regimen, 5 (42%) patients reached the therapeutic target. Conclusion Using the one-compartment model, we evaluate the pharmacokinetic parameters of vancomycin in pediatric patients after liver transplantation. Most of patients did not reach the therapeutic target with empirical regimen, so it is prudent to monitor the exposure to vancomycin directly by AUC/MIC ratio to maximize antimicrobial efficacy. Disclosures All Authors: No reported disclosures

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A Compositive Strategy to Study the Pharmacokinetics of TCMs: Taking Coptidis Rhizoma, and Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma as Examples

Molecules ◽

10.3390/molecules23082042 ◽

2018 ◽

Vol 23 (8) ◽

pp. 2042 ◽

Cited By ~ 2

Author(s):

Qiao Li ◽

Yan Yang ◽

Ting Zhou ◽

Rui Wang ◽

Na Li ◽

...

Keyword(s):

Area Under The Curve ◽

Simple Calculation ◽

Systemic Circulation ◽

Pharmacokinetic Studies ◽

Sufficient Information ◽

Blood Concentrations ◽

Glycyrrhizae Radix ◽

Pharmacokinetic Properties ◽

Coptidis Rhizoma

Pharmacokinetic studies are crucial for elucidating the effective constituents and formula compatibility of traditional Chinese medicines (TCMs). However, studies have usually been limited to single dosages and detection of systemic blood concentrations. To obtain comprehensive pharmacokinetic information, here we propose a multi-dosage and multi-sampling (blood from portal vein or systemic circulation, and liver) strategy to comparatively study the pharmacokinetics of multi-form TCMs, i.e., pure constituents, TCMs, or TCM formula extracts. Based on this strategy, we studied the pharmacokinetics of pure berberine, berberine in Coptidis Rhizoma (CRE), and berberine in Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extracts (CR-GRE). After simple calculation and comparison of the obtained area under the curve (AUC) values, the results revealed the drastically different pharmacokinetic properties of pure berberine compared to CRE and CR-GRE. The results contribute to explaining the pharmacological loss of berberine activity after purification and the compatibility of the CR-GR drug pair. The results also innovatively showed that it was intestinal absorption that differentiated the pharmacokinetics of CRE and pure berberine, and CRE and CR-GRE. In conclusion, we propose a composite strategy to comparatively study the pharmacokinetics of TCMs, which could provide sufficient information to obtain a comprehensive view, before follow-up mechanism-of-action studies.

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Post-transplant cyclophosphamide in matched and haploidentical transplant recipients receiving myeloablative timed sequential busulfan conditioning regimen: Results of a phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7007 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7007-7007

Author(s):

Uday R. Popat ◽

Rohtesh S. Mehta ◽

Roland Bassett ◽

Amanda Leigh Olson ◽

Amin Majid Alousi ◽

...

Keyword(s):

Phase Ii ◽

Disease Risk ◽

Phase Ii Study ◽

Risk Index ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Area Under The Curve ◽

Pharmacokinetic Studies ◽

Target Area ◽

Post Transplant

7007 Background: Myeloablative stem cell transplants have a lower rate of relapse than reduced intensity regimens. Timed sequential busulfan (TSB) with fludarabine (Flu) is a promising myeloablative regimen for patients undergoing matched sibling (MSD) or unrelated (MUD) donor transplantation (HCT) with low non-relapse mortality (NRM) (Popat et al Lancet Haematology 2018), but was not tested in haploidentical (haplo). Also, whether this approach can be used with post-transplant cyclophosphamide (PTCy) in MSD, MUD and haplo HCT is unknown. To address these issues, we conducted a prospective phase II study. Methods: Patients with hematological malignancies with MSD, MUD or haplo donor were eligible. They received fixed doses of Busulfan(BU) 80mg/m2 either on day -13 and -12 (n=45) or on -20 and -13 (n=10). Then, Flu 40mg/m2 was given on day -6 to -2 followed by Bu dosed to achieve target area under the curve (AUC) of 20,000 umol/min for the whole course based on pharmacokinetic studies. Thiotepa 5mg/kg was given on day -7 to haplo group. GVHD prophylaxis was PTCy 50mg/kg on day 3 and 4 and tacrolimus. Haplo and later MUD recipients also received mycophenolate mofetil. Results: 55 patients with a median age of 47 (15-65) years were enrolled. 30 patients had AML or MDS, 9 CML or MPD, 5 lymphoma, 5 myeloma and 6 ALL. About half had haplo 26 (47%); others had MUD 18 (33%) or MSD 11(20%). Disease risk index was high in 18 (32%), intermediate in 32 (58%), and low in 5 (9%) patients. Comorbidity score was ≥3 in 22 (40%) patients. With a median follow up of 17 months (5-28), 1-year OS, PFS, NRM and relapse rates were 71% (60-84%), 63% (51-77%), 20% (9-31%), and 17% (7-27%), respectively [Table]. There were no graft failures. Day 100 grade II-IV and III-IV acute GVHD rates were 38% (25-51%) and 9% (95% CI 1-17%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 10% (2-28%) and 8% (0-15%), respectively. 1-year OS in MSD, MUD and haplo groups were 91% (75-100%), 72% (54-96%), and 62% (45-83%) respectively (P=0.11). Conclusions: Myeloablative TSB with PTCy is feasible in MSD, MUD and haplo HCT. It lowers the incidence of severe acute and chronic GVHD without apparent increase in relapse. Clinical trial information: NCT02861417. [Table: see text]

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Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy166 ◽

2018 ◽

Vol 34 (10) ◽

pp. 1766-1772 ◽

Cited By ~ 3

Author(s):

Lama M Hsaiky ◽

Francine D Salinitri ◽

Judy Wong ◽

Sin-Ling T Jennings ◽

Neha H Desai ◽

...

Keyword(s):

Half Life ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Optimal Dose ◽

Hemodialysis Patients ◽

Pharmacokinetic Parameters ◽

Intermittent Hemodialysis ◽

Pharmacokinetic Studies ◽

Open Label ◽

Serious Adverse Events

Abstract Background Previous pharmacokinetic studies demonstrated an increase in serum ertapenem concentrations with decreasing kidney function, including patients receiving renal replacement therapy. This study evaluated the pharmacokinetic parameters of ertapenem in patients receiving hemodialysis. Methods This prospective, single-center, open-label study examined the pharmacokinetics of a single intravenous (IV) dose of ertapenem 1 g in seven hospitalized noninfected patients undergoing hemodialysis. Blood samples were collected prior to ertapenem administration and at 0.5, 1, 2, 6, 12 and 48 hours (h) after administration. Ertapenem concentrations were determined by validated liquid chromatography mass spectrometry assay. Results Following an IV bolus of 1 g ertapenem, plasma concentrations declined relatively slowly with a mean ±standard deviation (SD) elimination half-life of 19.3 ±6.6 h. Plasma concentrations were similar in all subjects, with maximum mean plasma concentration observed of 343±48 µg/mL postdose. The mean ±SD values for systemic plasma clearance (CL) and volume of distribution at steady state (Vss) were 2±0.5 mL/min and 3295±1187 mL, respectively. The area under the curve for 0 h–∞ (AUCinf) was 7494 ±1424 h•µg/mL. No gender effect was observed and no serious adverse events were reported. Conclusions Ertapenem half-life was prolonged in hemodialysis patients. Considering the nonrenal clearance and the expected 70% removal with high-efficacy hemodialysis, the dose of 1 g ertapenem, three times weekly, after hemodialysis may produce pharmacodynamically sufficient exposure for potential antimicrobial efficacy. Further studies are warranted to assess the clinical efficacy and safety of this dose with prolonged duration of therapy.

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Glucuronidation and its effect on the bioactivity of amentoflavone, a biflavonoid from Ginkgo biloba leaves

Journal of Pharmacy and Pharmacology ◽

10.1111/jphp.13247 ◽

2020 ◽

Cited By ~ 2

Author(s):

Lili Gan ◽

Jiating Ma ◽

Guoquan You ◽

Jinxia Mai ◽

Zhaoyu Wang ◽

...

Keyword(s):

Antioxidant Activity ◽

Anticancer Activity ◽

Ginkgo Biloba ◽

Metabolic Profile ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Pharmacokinetic Studies ◽

Significant Difference ◽

Dietary Flavonoid ◽

U251 Cells

Abstract Objectives Ginkgo biloba leaves contain amentoflavone (AMF), a dietary flavonoid that possesses antioxidant and anticancer activity. Flavonoids are extensively subjected to glucuronidation. This study aimed to determine the metabolic profile of AMF and the effect of glucuronidation on AMF bioactivity. Methods A pharmacokinetic study was conducted to determine the plasma concentrations of AMF and its metabolites. The metabolic profile of AMF was elucidated using different species of microsomes. The antioxidant activity of AMF metabolites was determined using DPPH/ABTS radical and nitric oxide assays. The anticancer activity of AMF metabolites was evaluated in U87MG/U251 cells. Key findings Pharmacokinetic studies indicated that the oral bioavailability of AMF was 0.06 ± 0.04%, and the area under the curve of the glucuronidated AMF metabolites (410.938 ± 62.219 ng/ml h) was significantly higher than that of AMF (194.509 ± 16.915 ng/ml h). UGT1A1 and UGT1A3 greatly metabolized AMF. No significant difference was observed in the antioxidant activity between AMF and its metabolites. The anticancer activity of AMF metabolites significantly decreased. Conclusions A low AMF bioavailability was due to extensive glucuronidation, which was mediated by UGT1A1 and UGT1A3. Glucuronidated AMF metabolites had the same antioxidant but had a lower anticancer activity than that of AMF.

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Human Pharmacokinetics of l-3,4-Dihydroxyphenylalanine Studied with Microdialysis

Clinical Chemistry ◽

10.1093/clinchem/45.10.1813 ◽

1999 ◽

Vol 45 (10) ◽

pp. 1813-1820 ◽

Cited By ~ 9

Author(s):

Nil Dizdar ◽

Anita Kullman ◽

Björn Norlander ◽

Jan-Edvin Olsson ◽

Bertil Kågedal

Keyword(s):

Protein Binding ◽

Parkinson Disease ◽

Healthy Subjects ◽

Rating Scale ◽

Area Under The Curve ◽

Disease Stage ◽

Control Group ◽

Pharmacokinetic Studies ◽

Human Pharmacokinetics ◽

Serum Samples

Abstract Background: Intravenous and subcutaneous microdialysis was performed to compare the free concentrations and pharmacokinetics of l-3,4-dihyroxyphenylalanine (l-dopa) in blood and tissue in healthy subjects and in patients with Parkinson disease. Methods: Nine healthy volunteers and 10 patients with Parkinson disease, stage 1.5–2 according to the Hoehn-Yahr rating scale, took part of the study. In the patient group subcutaneous microdialysis and ordinary blood sampling were performed, whereas in the control group intravenous microdialysis was also performed. Microdialysis samples were collected in fractions of 15 min. The first two fractions were collected for analysis of basal concentrations. A blood sample was also taken. The patients were then given one tablet of Madopar® (100 mg of l-dopa and 25 mg of benserazide), and the microdialysis was continued for another 210 min. Blood samples were obtained at 30-min intervals. Results: The serum samples gave a significantly higher mean area under the curve (AUC; 491 ± 139 μmol · min/L) than that for intravenous dialysates (235 ± 55.3 μmol · min/L), suggesting a protein binding of 50%. The l-dopa concentrations from the subcutaneous dialysates matched those from the intravenous dialysates, indicating rapid distribution of l-dopa to the tissues. Conclusions: Parkinsonian patients in early stages of the disease have a pharmacokinetic pattern of free l-dopa similar to that of healthy subjects. Comparison of AUCs from microdialysis with ordinary serum analysis revealed data indicating significant protein binding. Microdialysis is a suitable and easily applied tool in pharmacokinetic studies.

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