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

2020 ◽  
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.

scholarly journals Pharmacodynamics of Five Anthraquinones (Aloe-emodin, Emodin, Rhein, Chysophanol, and Physcion) and Reciprocal Pharmacokinetic Interaction in Rats with Cerebral Ischemia

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1898 ◽  
Author(s):  
Rong-Rong Li ◽  
Xue-Fang Liu ◽  
Su-Xiang Feng ◽  
Sheng-Nan Shu ◽  
Pei-Yang Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Plasma Exposure ◽  
Significant Difference ◽  
Aloe Emodin ◽  
Exposure Levels

(1) Background: Rhubarb anthraquinones—a class of components with neuroprotective function—can be used to alleviate cerebral ischemia reperfusion injury. (2) Methods: The three pharmacodynamic indicators are neurological function score, brain water content, and cerebral infarction area; UPLC-MS/MS was used in pharmacokinetic studies to detect plasma concentrations at different time points, and DAS software was used to calculate pharmacokinetic parameters in a noncompartmental model. (3) Results: The results showed that the pharmacodynamics and pharmacokinetics of one of the five anthraquinone aglycones could be modified by the other four anthraquinones, and the degree of interaction between different anthraquinones was different. The chrysophanol group showed the greatest reduction in pharmacodynamic indicators comparing with other four groups where the rats were administered one of the five anthraquinones, and there was no significant difference between the nimodipine group. While the Aloe-emodin + Physcion group showed the most obvious anti-ischemic effect among the groups where the subjects were administered two of the five anthraquinones simultaneously. Emodin, rhein, chrysophanol, and physcion all increase plasma exposure levels of aloe-emodin, while aloe-emodin lower their plasma exposure levels. (4) Conclusions: This experiment provides a certain preclinical basis for the study of anthraquinone aglycones against cerebral ischemia and a theoretical basis for the study of the mechanism of interaction between anthraquinones.

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

1999 ◽  
Vol 96 (2) ◽  
pp. 199-207 ◽  
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.

Pharmacokinetic comparison of two buprenorphine formulations after buccal administration in healthy male cats

2017 ◽  
Vol 20 (4) ◽  
pp. 312-318 ◽  
Author(s):  
Brett M Gulledge ◽  
Kristen M Messenger ◽  
Karen K Cornell ◽  
Heather Lindell ◽  
Chad W Schmiedt
Keyword(s):  
Liquid Chromatography ◽  
Maximum Concentration ◽  
High Performance ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Storage Condition ◽  
Healthy Male ◽  
Limit Of Quantification ◽  
Significant Difference ◽  
Extent Of Absorption

Objectives The objective of this study was to compare the pharmacokinetics of compounded and commercially available aqueous formulations of buprenorphine after a single buccal dose to healthy cats and to evaluate the concentrations of a compounded buprenorphine solution over 21 days when stored at room temperature (RT; 22–24°C) with exposure to light or when refrigerated at 4°C while protected from light. Methods Six young healthy male cats were administered single buccal doses of compounded and commercially available formulations of buprenorphine (0.03 mg/kg) using a randomized, blinded, two-period crossover design. Blood samples were obtained over a 24 h period and plasma buprenorphine concentrations were determined using ultra-high-pressure liquid chromatography with mass spectrometry detection. Three batches of the compounded formulation were stored at RT or 4°C and aliquots were evaluated over 21 days for buprenorphine concentration using high-performance liquid chromatography with fluorescence detection. Results Plasma concentrations of buprenorphine were above the limit of quantification up to 6 h in some cats and up to 3 h in all cats. The area under the curve was significantly less for the compounded formulation ( P = 0.004). A significant difference was not detected between formulations for time to maximum concentration ( P = 0.11), maximum concentration ( P = 0.06), half-life ( P = 0.88) and mean residence time ( P = 0.57). Buprenorphine concentration in the compounded formulation was not affected by storage condition or time and remained between 90% and 110% of the target concentration at all time points. Conclusions and relevance A buprenorphine solution prepared from sublingual tablets is absorbed after buccal administration in healthy cats. The extent of absorption is significantly less than that of the commercially available formulation. The compounded solution maintains an acceptable buprenorphine concentration for at least 21 days when stored at RT or refrigerated.

Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients

2018 ◽  
Vol 34 (10) ◽  
pp. 1766-1772 ◽  
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.

scholarly journals Pharmacokinetics of Posaconazole Suspension in Lung Transplant Patients with and without Cystic Fibrosis

2016 ◽  
Vol 60 (6) ◽  
pp. 3558-3562 ◽  
Author(s):  
Hongfei Zhang ◽  
M. Hong Nguyen ◽  
Cornelius J. Clancy ◽  
Rujuta Joshi ◽  
Wenchen Zhao ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Transplant ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Treatment Strategies ◽  
Area Under The Curve ◽  
Therapeutic Drug ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Average Dose

Invasive fungal infections (IFIs) are common among lung transplant recipients (LTRs). Posaconazole is an important antifungal agent for both prophylaxis and treatment of IFIs; however, detailed pharmacokinetic data are limited among LTRs, particularly those with cystic fibrosis (CF). Our objective was to conduct a pharmacokinetic study of posaconazole oral suspension among LTRs, with particular attention to patients with CF. We enrolled 20 LTRs, 7 with CF and 13 with other underlying lung diseases. Average daily doses in CF and non-CF patients were 829 and 862 mg, respectively. After ≥5 days of treatment, only 4 patients had average plasma concentrations of >0.7 μg/ml. Average steady-state plasma concentrations were 61% lower in CF patients (0.233 μg/ml) than in non-CF LTRs (0.594 μg/ml;P= 0.03). The average dose-normalized plasma area-under-the-curve (AUC) values were also lower in CF (0.007 h·μg/ml) than in non-CF LTRs (0.02 h·μg/ml;P= 0.02). The weight-normalized apparent oral clearance values were 2.51 and 0.74 liters/h/kg among CF and non-CF LTRs, respectively (P= 0.005). Despite significant interpatient variability, plasma trough concentrations were strongly correlated with posaconazole AUC across all LTRs (r2= 0.95,P< 0.0001). Taken together, our study highlights a critical need to incorporate new formulations of posaconazole into prophylaxis and treatment strategies for LTRs, particularly those with CF. Future pharmacokinetic studies of both tablet and intravenous formulations must consider LTR-specific factors and incorporate a therapeutic drug monitoring plan in this patient population.

Clinical Effects and Maternal and Fetal Plasma Concentrations of 0.5% Epidural Levobupivacaine versus Bupivacaine for Cesarean Delivery

1999 ◽  
Vol 90 (6) ◽  
pp. 1596-1601. ◽  
Author(s):  
Angela M. Bader ◽  
Lawrence C. Tsen ◽  
William R. Camann ◽  
Elizabeth Nephew ◽  
Sanjay Datta
Keyword(s):  
Cesarean Delivery ◽  
Epidural Anesthesia ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Clinical Effects ◽  
Elective Cesarean Delivery ◽  
Significant Difference ◽  
Elective Cesarean

Background Bupivacaine exists as a mixture of two enantiomers, levobupivacaine and dexbupivacaine. Data suggest that levobupivacaine has equal local anesthetic potency, with reduced potential for central nervous system and cardiovascular toxicity. The present study compares the efficacy of 0.5% levobupivacaine with 0.5% bupivacaine for epidural anesthesia in parturients undergoing elective cesarean delivery. Methods Sixty healthy obstetric patients undergoing elective cesarean delivery with epidural anesthesia completed the study. Patients were randomized to receive 30 ml of either 0.5% levobupivacaine or 0.5% bupivacaine in a double-blind fashion. The efficacy endpoint measures included onset, offset, and quality of anesthesia. Neonatal blood gas analyses, Apgar score determinations, and neurobehavioral examinations were performed. Venous samples for pharmacokinetic studies and serial electrocardiograms were obtained in 10 patients in each group. Results Levels of sensory block, motor block, muscle relaxation, and overall quality of anesthesia did not differ between groups. The frequency of hypotension was 84.4% in the levobupivacaine group and 100% for the bupivacaine group (P &lt; or = 0.053). No significant difference in observed maximum concentration of drug after dosing or area under the plasma drug concentration versus time curve were seen. The maximum concentrations were 1.017 and 1.053 microg/ml, and the areas were 4.082 and 3.765 h(microg/ml) for the levobupivacaine and bupivacaine groups, respectively. Umbilical vein-to-maternal vein ratios were 0.303 for the levobupivacaine group and 0.254 for the bupivacaine group. Conclusions The use of epidural 0.5% levobupivacaine for cesarean delivery results in equally efficacious anesthesia compared with 0.5% bupivacaine. Pharmacokinetic parameters were similar in the two groups.

Phase I clinical and pharmacokinetic study of oral etoposide phosphate.

1995 ◽  
Vol 13 (1) ◽  
pp. 200-209 ◽  
Author(s):  
C Sessa ◽  
M Zucchetti ◽  
T Cerny ◽  
O Pagani ◽  
F Cavalli ◽  
...  
Keyword(s):  
Phase I ◽  
Intravenous Administration ◽  
High Performance ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Oral Etoposide ◽  
Validation Data ◽  
Etoposide Phosphate

PURPOSE To determine the bioavailability (F) and the pharmacokinetic profile of both etoposide and its prodrug, etoposide phosphate, after oral and intravenous administration of etoposide phosphate, and to determine the maximum-tolerable dose (MTD) of oral etoposide phosphate administered daily for 5 consecutive days every 3 weeks. In addition, we sought to develop and validate two limited-sampling models (LSMs) to predict the etoposide area under the curve (AUC) 24 hours after administration of oral and intravenous etoposide phosphate. PATIENTS AND METHODS In the F part of the study, patients were assessed for pharmacokinetic studies after one oral and one intravenous administration of the same dose of etoposide phosphate. Etoposide phosphate and etoposide plasma concentrations were assayed by high-performance liquid chromatography (HPLC). To develop LSMs after oral and intravenous administration, patients were randomized between the training and validation data sets. In the phase I part of the study, which followed the F part, the dose of etoposide phosphate was escalated from 50 mg/m2/d for etoposide equivalents for 5 days to 220 mg/m2/d for 5 days. RESULTS Forty adult patients with solid tumors or lymphoma entered the study and 35 were assessable for toxicity. The MTDs were defined as 175 mg/m2 and 220 mg/m2 in previously treated and untreated patients, respectively. Neutropenia was dose-limiting, with high interpatient variability. Within 15 minutes after intravenous administration, etoposide phosphate was no longer detectable in plasma, and it was never detectable after oral administration. Plasma concentrations and pharmacokinetic parameters of etoposide following etoposide phosphate were comparable to those reported for etoposide. The relative F (mean +/- SD) of etoposide after oral etoposide phosphate was 76 +/- 27%, with a range of 37% to 144%. CONCLUSION The clinical and pharmacokinetic results of this study confirm the prodrug hypothesis of etoposide phosphate. Although firm conclusions cannot be drawn, the F of oral etoposide phosphate seems to be comparable to or only slightly better than that of oral etoposide.

scholarly journals Effects of 5′-uridylic acid feeding on postprandial plasma concentrations of GH, insulin and metabolites in young calves

2005 ◽  
Vol 186 (1) ◽  
pp. 157-163 ◽  
Author(s):  
K Katoh ◽  
K Yoshioka ◽  
H Hayashi ◽  
T Mashiko ◽  
M Yoshida ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Insulin Level ◽  
Postprandial Glucose ◽  
The Body ◽  
Nonesterified Fatty Acid ◽  
Control Group ◽  
Bull Calves ◽  
Significant Difference ◽  
Igf I

Postprandial changes in plasma concentrations of GH, insulin, IGF-I, leptin and metabolites were compared between young Holstein bull calves fed with milk alone (control group) and with milk+5′-uridylic acid (UMP) (UMP group). UMP (2 g/day) was given with milk at 0830 h and 1530 h for 11 days from the 4th to the 14th day after birth. The perirenal fat weight was significantly lower in the UMP group than in the control group, but there was no significant difference in the weights of the liver, spleen and heart between the groups. Basal GH concentrations in the UMP group were slightly higher, but the postprandial increase in plasma insulin level and the area under the curve for insulin in the UMP group were significantly lower than those in the control group. There was no significant difference in IGF-I levels between the groups. In addition, the postprandial glucose concentrations were lower in the UMP group as reflected by the insulin level, and nonesterified fatty acid concentrations were not different. In the muscle (M. longissimus thoracis) sampled at 14 days of age, the triacylglycerol (TAG) content was significantly greater but glycogen content was significantly lower in the UMP group than in the control group. From these results, we have concluded that feeding 5′-UMP at 2 g/day for 11 days significantly alters TAG accumulation in the body and plasma concentrations of GH and insulin in young bull calves.

Pulmonary Disposition of Propofol in Surgical Patients

2000 ◽  
Vol 93 (4) ◽  
pp. 986-991 ◽  
Author(s):  
Yan-Ling He ◽  
Hiroshi Ueyama ◽  
Chikara Tashiro ◽  
Takashi Mashimo ◽  
Ikuto Yoshiya
Keyword(s):  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Back Diffusion ◽  
Blood Samples ◽  
Arterial Blood ◽  
Pulmonary Uptake ◽  
Human Lungs ◽  
Infusion Study ◽  
Significant Difference ◽  
First Pass

Background The lungs have been mentioned as a possible site contributing to the extrahepatic clearance of propofol. The objective of the present study was to clarify the pulmonary disposition of propofol directly in human lungs by investigating both the first-pass uptake and pulmonary extraction at pseudo-steady state. Methods Nine patients were enrolled in the first-pass uptake study. Propofol (5 mg) and indocyanine green (ICG; 15 mg) were simultaneously administered via a central venous catheter within 1 s, and sequential arterial blood samples were obtained from the radial artery at 1-s intervals up to 45 s. Eleven patients were included in the infusion study, and propofol was infused via the jugular vein at a rate of 50 microgram. kg-1. min-1. Blood samples were simultaneously collected from pulmonary and radial arteries up to 60 min. Results A pronounced difference in the dilution curves between propofol and ICG was observed, and 28.4 +/- 11.6% (mean +/- SD) of propofol was taken up during the single passage through the human lung. The mean pulmonary transit time of propofol (31.3 +/- 6.0 s) was significantly longer than that of ICG (22.4 +/- 2.7 s; P &lt; 0.01), indicating that some of the propofol trapped by lungs returned to the circulation by back diffusion. In the constant infusion study, no significant differences were observed with the plasma concentrations of propofol between pulmonary and radial arteries except for that at 2 min. The area under the curve of pulmonary and radial arterial concentration curves to 60 min were 59.1 +/- 14.8 and 56.8 +/- 12.5 microg. ml-1. min-1, respectively. No significant difference was observed with the area under the curve, suggesting that metabolism was not involved in the pulmonary uptake in human lungs. Conclusions Most of the propofol that undergoes pulmonary uptake during the first pass was released back to the circulation by back diffusion. Metabolism was not involved in the pulmonary uptake in human lungs.

scholarly journals The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers

2021 ◽  
Author(s):  
Ida Tylleskar ◽  
Sissel Skarra ◽  
Arne Kristian Skulberg ◽  
Ola Dale
Keyword(s):  
Maximum Concentration ◽  
Intranasal Administration ◽  
Area Under The Curve ◽  
Pharmacokinetic Interaction ◽  
Intramuscular Administration ◽  
Nasal Administration ◽  
Pharmacokinetic Studies ◽  
Remifentanil Infusion ◽  
Human Volunteers ◽  
Significant Difference

Abstract Purpose Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. Methods We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone-3-glucuronide (N3G), the main metabolite of naloxone, with or without exposure to remifentanil. To enable direct comparison of the three studies, the data are presented as metabolic ratios (ratio of metabolite to mother substance, N3G/naloxone) and dose-corrected values of the area under the curve and maximum concentration (Cmax). Results Under remifentanil exposure, the time to maximum concentration (Tmax) for N3G was significantly higher for intranasal administration of 71 min compared to intramuscular administration of 40 min. The dose-corrected Cmax of N3G after intranasal administration of naloxone under remifentanil exposure was significantly lower (4.5 ng/mL) than in subjects not exposed to remifentanil (7.8–8.4 ng/mL). The metabolic ratios after intranasal administration rose quickly after 30–90 min and were 2–3 times higher at 360 min compared to intravenous and intramuscular administration. Remifentanil exposure resulted in a much slower increase of the N3G/naloxone ratio after intranasal administration compared to intranasal administration with the absence of remifentanil. After remifentanil infusion was discontinued, this effect gradually diminished. From 240 min there was no significant difference between the ratios observed after intranasal naloxone administration. Conclusion Remifentanil increases the bioavailability of naloxone after nasal administration by reducing the pre-systemic metabolism of the swallowed part of the nasal dose.

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