scholarly journals Enhanced Oral Bioavailability of Domperidone with Piperine in Male Wistar Rats: Involvement of CYP3A1 and P-gp Inhibition

2017 ◽  
Vol 20 ◽  
pp. 28 ◽  
Author(s):  
Bhargavi Latha Athukuri ◽  
Prasad Neerati
Keyword(s):  
Plasma Concentration ◽  
Oral Bioavailability ◽  
Wistar Rats ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Elimination Rate ◽  
Intestinal Transport ◽  
Control Group ◽  
Maximum Plasma ◽  
Male Wistar Rats

Purpose: Domperidone is a commonly used antiemetic drug. The oral bioavailability of domperidone is very low due to its rapid first pass metabolism in the intestine and liver. Piperine, the main alkaloid present in black pepper has been reported to show inhibitory effects on Cytochrome P-450 (CYP-450) enzymes and P-glycoprotein (P-gp). In the present study we investigated the effect of piperine pretreatment on the intestinal transport and oral bioavailability of domperidone in male Wistar rats. Methods: The intestinal transport of domperidone was evaluated by an in-vitro non-everted sac method and in-situ single pass intestinal perfusion (SPIP) study. The oral pharmacokinetics of domperidone was evaluated by conducting oral bioavailability study in rats. Results: A statistically significant improvement in apparent permeability (Papp) was observed in rats pretreated with piperine compared to the respective control group. The effective permeability (Peff) of domperidone was increased in the ileum of the piperine treated group. Following pretreatment with piperine, the peak plasma concentration (Cmax) and area under the concentration- time curve (AUC) were significantly increased. A significant decrease in time to reach maximum plasma concentration (Tmax), clearance and elimination rate constant (Kel) was observed in rats pretreated with piperine. Conclusions: Piperine enhanced the oral bioavailability of domperidone by inhibiting CYP3A1 and P-gp in rats. This observation suggests the possibility that the combination of piperine with other CYP3A4 and P-gp dual substrates may also improve bioavailability. Further clinical studies are recommended to verify this drug interaction in human volunteers and patients. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: involvement of CYP2D6 inhibition

2016 ◽  
Vol 31 (4) ◽  
Author(s):  
Bhargavi Latha Athukuri ◽  
Prasad Neerati
Keyword(s):  
Drug Interactions ◽  
Gallic Acid ◽  
Ellagic Acid ◽  
Oral Bioavailability ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Intestinal Transport ◽  
Herbal Drug ◽  
Male Wistar Rats ◽  
Mixed Function Oxidase System

Abstract Background: Cytochrome P450-2D6 (CYP2D6), a member of the CYP450 mixed function oxidase system, is an important CYP isoform with regard to herbal-drug interactions and is responsible for the metabolism of nearly 25% of drugs. Until now, studies on the effects of various phytochemicals on CYP2D6 activity Methods: The intestinal transport of metoprolol was assessed by conducting an Results: After pretreatment with gallic acid and ellagic acid, no significant change in effective permeability of metoprolol was observed at the ileum part of rat intestine. A significant improvement in the peak plasma concentration (C Conclusions: Gallic acid and ellagic acid significantly enhanced the oral bioavailability of metoprolol by inhibiting CYP2D6-mediated metabolism in the rat liver. Hence, adverse herbal-drug interactions may result with concomitant ingestion of gallic acid and ellagic acid supplements and drugs that are CYP2D6 substrates. The clinical assessment of these interactions should be further investigated in human volunteers.

Pharmacokinetics of solid lipid Boswellia serrata particles in healthy subjects

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Preeti D. Kulkarni ◽  
Neena D. Damle ◽  
Lal Hingorani ◽  
Vaidhun H. Bhaskar ◽  
Minal R. Ghante ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Oral Bioavailability ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Maximum Plasma ◽  
Boswellic Acid ◽  
Healthy Human ◽  
Boswellia Serrata ◽  
Solid Lipid ◽  
Human Volunteers

Abstract Objectives The anti-inflammatory activity of Boswellia serrata extracts (BSE) is well known. BSE comprises boswellic acids (BA) such as 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) as major constituents. One of the limitations of BAs is their poor oral bioavailability. The aim of the study was to prepare solid lipid particles of Boswellia serrata extract (SLBSP) to enhance the bioavailability of BAs. Methods The pharmacokinetic profile of BAs was studied in 10 healthy human volunteers following a single oral dose of 333 mg of SLBSP. Pharmacokinetic blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h post drug administration. Plasma KBA and AKBA levels were measured using a validated LC-MS/MS method. Pharmacokinetics parameters were estimated using Pheonix WinNonlin (Build 6.4.0.768) software. Results Ten healthy human volunteers were included and peak plasma concentration was achieved in 1.5 and 2.3 h for AKBA and KBA respectively. Maximum plasma concentration (C max) was 8.04 ± 1.67 ng/mL for AKBA and 23.83 ± 4.41 ng/mL for KBA whereas the corresponding area under the concentration-time curve (AUC) was 136.7 ± 56.77 ng/mL*h and 165.7 ± 24.5 ng/mL*h respectively. The elimination half-life (t 1/2) of AKBA and KBA was 6.8 ± 3.0 h and 2.45 ± 0.3 h respectively. Conclusions The SLBSP formulation of BSE showed enhanced oral bioavailability of BAs compared with historically reported data of unformulated BSE.

scholarly journals Comparative bioavailability study of phenytoin in healthy Nepalese volunteers

2019 ◽  
Vol 9 (1-s) ◽  
pp. 144-147
Author(s):  
DIllisher Rai ◽  
Gajendra Prasad Rauniar
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Elimination Rate ◽  
P Value ◽  
Maximum Plasma ◽  
Time Curve ◽  
Oral Tablet ◽  
Concentration Time ◽  
Plasma Concentration Time Curve

Our study aimed to assess and compare the bioavailability of Eptoin 100 mg and Epileptin 100mg tablets in Nepalese healthy volunteers. A randomized, two-treatment cross-over study with two weeks’ wash-out period was conducted in 12 healthy non-smoker and non-alcoholic Nepalese male volunteers over a period of 6 months in the department of Clinical Pharmacology and Therapeutic at B. P. Koirala Institute of Health Sciences, Dharan, Nepal after approval from the Institutional Review Committee. The participants were randomized using sealed envelope system and received a single 100 mg oral tablet of either of the formulations with a two week washout period. Blood samples were collected predose and at regular intervals postdose upto 72 hours. Plasma phenytoin levels were estimated by reverse phase high performance liquid chromatography. The analytical method was validated prior to the start of study. Cmax (Peak Plasma Concentration), Tmax (Time to achieve maximum Plasma Concentration), AUC0-72 (Area under plasma concentration time curve 0 to 72 hours), AUC0-∞ (Area under plasma concentration time curve 0 to ∞) and T½ (Elimination half-life) and Kel (Elimination rate constant) were calculated and 80-120% margin (90% confidence interval) was used to assess bioequivalence. ANOVA test was used to analyze the data at P-value of 0.05. All volunteers completed the study. The log-transformed values of Cmax, Tmax, AUC0-t, and AUC0-∞ of the both formulations were within the specified limits and were bioequivalent according to the regulatory definition of bioequivalence based on the rate and extent of absorption. Both products can be considered equally effective in medical practice. Keywords: Bioavailability, Bioequivalence, healthy volunteer, Nepal, phenytoin sodium.

Pharmacokinetics of solid lipid Boswellia serrata particles in healthy subjects

2021 ◽  
Vol 36 (3) ◽  
pp. 215-221
Author(s):  
Preeti D. Kulkarni ◽  
Neena D. Damle ◽  
Lal Hingorani ◽  
Vaidhun H. Bhaskar ◽  
Minal R. Ghante ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Oral Bioavailability ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Maximum Plasma ◽  
Boswellic Acid ◽  
Healthy Human ◽  
Boswellia Serrata ◽  
Solid Lipid ◽  
Human Volunteers

Abstract Objectives The anti-inflammatory activity of Boswellia serrata extracts (BSE) is well known. BSE comprises boswellic acids (BA) such as 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) as major constituents. One of the limitations of BAs is their poor oral bioavailability. The aim of the study was to prepare solid lipid particles of Boswellia serrata extract (SLBSP) to enhance the bioavailability of BAs. Methods The pharmacokinetic profile of BAs was studied in 10 healthy human volunteers following a single oral dose of 333 mg of SLBSP. Pharmacokinetic blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h post drug administration. Plasma KBA and AKBA levels were measured using a validated LC-MS/MS method. Pharmacokinetics parameters were estimated using Pheonix WinNonlin (Build 6.4.0.768) software. Results Ten healthy human volunteers were included and peak plasma concentration was achieved in 1.5 and 2.3 h for AKBA and KBA respectively. Maximum plasma concentration (C max) was 8.04 ± 1.67 ng/mL for AKBA and 23.83 ± 4.41 ng/mL for KBA whereas the corresponding area under the concentration-time curve (AUC) was 136.7 ± 56.77 ng/mL*h and 165.7 ± 24.5 ng/mL*h respectively. The elimination half-life (t 1/2) of AKBA and KBA was 6.8 ± 3.0 h and 2.45 ± 0.3 h respectively. Conclusions The SLBSP formulation of BSE showed enhanced oral bioavailability of BAs compared with historically reported data of unformulated BSE.

Safety, Tolerability, and Pharmacokinetics of Sumatriptan in Healthy Subjects Following Ascending Single Intranasal Doses and Multiple Intranasal Doses

Cephalalgia ◽  
1997 ◽  
Vol 17 (4) ◽  
pp. 541-550 ◽  
Author(s):  
KHP Moore ◽  
EK Hussey ◽  
S Shaw ◽  
E Fuseau ◽  
C Duquesnoy ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Adverse Events ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Dose Range ◽  
Maximum Plasma ◽  
Multiple Doses ◽  
To Receive ◽  
Intranasal Spray ◽  
Female Subjects

The delivery of sumatriptan doses intranasally could add greater flexibility in the treatment of migraine than is possible with the currently available subcutaneous and oral sumatriptan preparations. Two independent double-blind, randomized, placebo-controlled clinical studies were conducted to evaluate the safety, tolerability and pharmacokinetics of intranasally administered sumatriptan following ascending single doses (three different dose levels) and multiple doses. In the four-way crossover, ascending-dose study, 20 healthy female subjects were randomized to receive on separate occasions single intranasal spray doses of 5, 10, or 20 mg sumatriptan (as the hemisulphate salt) or placebo into one nostril. Adverse events were mild and consisted mainly of bitter taste at the back of the throat and events typical of sumatriptan administered by other routes (headache, lightheadedness and tingling). Area under the plasma sumatriptan concentration versus time curve (AUC) and peak plasma concentration (Cmax) increased with the dose. Dose proportionality was demonstrated between 5 and 10 mg but not across the dose range 5–20 mg. Time to maximum plasma concentration (tmax) was variable due to multiple peaking. The elimination half-life (t1/2), approximately 2 h, was unaffected by the magnitude of dose. In the two-period, multiple-dose, crossover study, 12 healthy adult male and female subjects were randomized to receive either sumatriptan hemisulphate 20 mg or placebo, administered intranasally as a spray three times a day for 4 days, The two dosing periods were separated by 3 to 14 days. Multiple doses of sumatriptan were well tolerated, with no serious adverse events occurring or withdrawals due to adverse events. All patients reported a mild to moderate drug-related disturbance of taste. Nasal examinations remained normal, and olfactory function was unaffected. The AUC over the first 8 h following dosing (AUC8) and fraction of the dose excreted in the urine (fe; 6.2% vs 3.6%) were similar on Days 1 and 4. Day 4 values were significantly higher (p0.05) for Cmax (16.9 ng/ml vs 13.1 ng/ml), renal clearance (Clr; 19.0 l/h vs 14.2 l/h), and t1/2 (2.18 h vs 1.93 h), and shorter for tmax (0.88 h vs 1.75 h). Some accumulation (22%) occurred over the 4 days of dosing. Serum concentrations of the pharmacologically inactive indole acetic acid metabolite of sumatriptan were fourfold to fivefold higher than corresponding sumatriptan concentrations. Overall, these studies show the sumatriptan intranasal spray formulation is well tolerated, allows rapid absorption of sumatriptan, and results in only a clinically insignificant degree of sumatriptan accumulation upon repeated dosing.

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

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.

Efficacy of guar gum-based ronidazole capsules as a treatment for Tritrichomonas foetus infection in cats

2016 ◽  
Vol 19 (2) ◽  
pp. 177-184 ◽  
Author(s):  
Aurélien Grellet ◽  
Seyf Eddine Makhlouf ◽  
Loic Desquilbet ◽  
Fani Hovhannessian ◽  
Cassandre Boogaerts ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Placebo Group ◽  
Plasma Concentration ◽  
Guar Gum ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Maximum Plasma Concentration ◽  
Maximum Plasma ◽  
Tritrichomonas Foetus ◽  
Significant Difference

Objectives The aims of the study were to determine the in vitro drug release of guar gum-coated capsules of ronidazole, and to evaluate the pharmacokinetics and efficacy of this formulation for the treatment of cats naturally infected with Tritrichomonas foetus. Methods The pharmacokinetics of ronidazole were evaluated in five healthy cats and five cats infected with T foetus. In a second step, the clinical efficacy of these capsules was evaluated by a controlled, randomised, double-blind clinical trial performed in 47 infected cats from French catteries. In this study, cats were randomly allocated to either the ronidazole treatment group (n = 25) or a placebo group (n = 22). Ronidazole (30 mg/kg) q24h for 14 days was administered to the treated cats. After 14 days of treatment, the presence of T foetus was tested by conventional PCR assay. Results In the pharmacokinetic study, a delayed peak plasma concentration was observed in healthy and infected cats, with no significant difference between these two groups (mean geometric mean of 9 h for time to maximum plasma concentration [Tmax], 21.6 µg/ml for time to maximum plasma concentration [Cmax] and 467.4 μg/h/ml for the area under the curve [AUC] in healthy cats; and 9.4 h for Tmax, 17.1 µg/ml for Cmax and 481 μg/h/ml for AUC in infected cats). In the clinical trial, T foetus was detected in 16% of cats from the treated group and 82% of cats from the placebo group at the end of the study ( P <0.001). No clinical signs of adverse drug reactions were observed. Conclusions and relevance Oral administration of guar gum-coated capsules of ronidazole at a dose of 30 mg/kg once daily for 14 days delays the peak plasma concentration and eradicates infection in most cases.

scholarly journals Effect of quercetin on the transport of ritonavir to the central nervous system in vitro and in vivo

2016 ◽  
Vol 66 (1) ◽  
pp. 97-107 ◽  
Author(s):  
Gongwen Liang ◽  
Na Li ◽  
Liping Ma ◽  
Zhonglian Qian ◽  
Yuwen Sun ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Tissue Distribution ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Phase 1 ◽  
Control Group ◽  
Intracellular Accumulation ◽  
Sprague Dawley ◽  
Time Curve

Abstract The aim of this study was to identify an effective flavonoid that could improve the intracellular accumulation of ritonavir in human brain-microvascular endothelial cells (HBMECs). An in vivo experiment on Sprague-Dawley rats was then designed to further determine the flavonoid’s impact on the pharmacokinetics and tissue distribution of ritonavir. In the accumulation assay, the intracellular leve l of ritonavir was increased in the presence of 25 mmol L−1 of flavonoids in HBMECs. Quercetin showed the strongest effect by improving the intracellular accumulation of ritonavir by 76.9 %. In the pharmacokinetic study, the presence of quercetin in the co-administration group and in the pretreatment group significantly decreased the area under the plasma concentration-time curve (AUC0–t) of ritonavir by 42.2 % (p < 0.05) and 53.5 % (p < 0.01), and decreased the peak plasma concentration (cmax) of ritonavir by 23.1 % (p < 0.05) and 45.8 % (p < 0.01), respectively, compared to the control group (ritonavir alone). In the tissue distribution study, the ritonavir concentration in the brain was significantly increased 2-fold (p < 0.01), during the absorption phase (1 h) and was still significantly higher (p < 0.05) during the distribution phase (6 h) in the presence of quercetin.

A Single Ascending Dose Study of Epigallocatechin Gallate in Healthy Volunteers

2003 ◽  
Vol 31 (2) ◽  
pp. 88-101 ◽  
Author(s):  
U Ullmann ◽  
J Haller ◽  
JP Decourt ◽  
N Girault ◽  
J Girault ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Time Course ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Epigallocatechin Gallate ◽  
Controlled Study ◽  
Maximum Plasma ◽  
Double Blind ◽  
The Mean ◽  
Oral Doses

This randomized, double-blind, placebo-controlled study assessed the safety, tolerability and plasma kinetic behaviour of single oral doses of 94% pure crystalline bulk epigallocatechin gallate (EGCG) under fasting conditions in 60 healthy male volunteers. In each group of 10 subjects, eight received oral EGCG in single doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg or 1600 mg, and two received placebo. Blood samples were taken at intervals until 26 h later. The area under the concentration-time curve from 0 h to infinity (AUC(0–∞)), the maximum plasma concentration ( Cmax) of EGCG, the time taken to reach the maximum concentration ( Tmax), and the terminal elimination half-life ( t1/2z) of EGCG were determined. Safety and tolerability were assessed. In each dosage group, the kinetic profile revealed rapid absorption with a one-peak plasma concentration versus time course, followed by a multiphasic decrease consisting of a distribution phase and an elimination phase. The mean AUC(0– ∞) of total EGCG varied between 442 and 10368 ng·h/ml. The according mean Cmax values ranged from 130 to 3392 ng/ml and were observed after 1.3–2.2 h. The mean t1/2z values were seen between 1.9 and 4.6 h. Single oral doses of EGCG up to 1600 mg were safe and very well tolerated.

Pengaruh Profilaksis Ekstrak Ubi Jalar Ungu (Ipomoea batatas L.) terhadap Kadar Malondialdehida Hepar Tikus Putih (Rattus norvegicus) Jantan Galur Wistar yang Diinduksi Karagenan

2018 ◽  
Vol 15 (2) ◽  
pp. 146
Author(s):  
BRILIAN DINANTI ◽  
FITRI HANDAJANI
Keyword(s):  
Sweet Potato ◽  
Ipomoea Batatas ◽  
Wistar Rats ◽  
Group Method ◽  
Control Group ◽  
Intraplantar Injection ◽  
Significant Difference ◽  
Male Wistar Rats ◽  
Potato Extract ◽  
Purple Sweet Potato

<p>Liver is an organ with complex metabolism. When the liver is inflamed, cellular immunity will defend against inflammatory agents by stimulating immune cells to produce reactive oxygen species (ROS). Excessive ROS accumulation cause oxydative stress with increased  liver malondialdehyde (MDA) level. Some researches showed that purple sweet potato contain flavonoids (anthocyanins) that functioned as antioxydants. This study aimed to show the prophylactic effect of purple sweet potato extract to the liver MDA level of male Wistar rats induced by carrageenan.</p><p>This study used post-only control group method using 18 male Wistar rats divided into 3 groups: group of rats without treatment, group of rats induced by 0,1 ml of 1% carrageenan by intraplantar injection on day-8, and group of rats given with 872 mg/kgBW of purple sweet potato extract for 7 days and induced by 0,1 ml of 1% carrageenan. In the end of the study, the liver MDA levels were measured by Thio-Barbituric Acid method on each groups.</p><p>The results of One-Way ANOVA test showed there was no significant difference (p = 0,290) between group of rats without treatment (<em>x̅</em>= 207,50) and group of rats induced by carrageenan (<em>x̅</em>=233,17). Then, there is no significant difference (p = 0.978) between group of rats induced by carrageenan and group of rats given with prophylactic purple sweet potato extract and induced by carrageenan (<em>x̅</em>= 232,50).</p><p>The conclusion of this study is giving intraplantar injection of carrageenan can increase liver MDA level insignificantly and giving prophylactic purple sweet potato extract has an effect to decrease the liver MDA level of rats induced by carragenan insignificantly because it contains anthocyanins as antioxidants.</p><p> </p><strong>Keywords: </strong>Liver, <em>Ipomoea batatas</em> L., Malondialdehyde, Anthocyanins

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