Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies

We aimed to develop a berberine formulation to enhance the intestinal absorption and plasma concentrations of berberine through the inhibition of P-glycoprotein (P-gp)-mediated efflux and the intestinal metabolism of berberine in rats. We used pluronic P85 (P85) and tween 80, which have the potential to inhibit P-gp and cytochrome P450s (i.e., CYP1A2, 2C9, 2C19, 2D6, and 3A4). A berberine-loaded mixed micelle formulation with ratios of berberine: P85: tween 80 of 1:5:0.5 (w/w/w) was developed. This berberine mixed micelle formulation had a mean size of 12 nm and increased the cellular accumulation of digoxin via P-gp inhibition. It also inhibited berberine metabolism in rat intestinal microsomes, without significant cytotoxicity, up to a berberine concentration of 100 μM. Next, we compared the pharmacokinetics of berberine and its major metabolites in rat plasma following the oral administration of the berberine formulation (50 mg/kg) in rats with the oral administration of berberine alone (50 mg/kg). The plasma exposure of berberine was significantly greater in rats administered the berberine formulation compared to rats administered only berberine, which could be attributed to the increased berberine absorption by inhibiting the P-gp-mediated berberine efflux and intestinal berberine metabolism by berberine formulation. In conclusion, we successfully prepared berberine mixed micelle formulation using P85 and tween 80 that has inhibitory potential for P-gp and CYPs (CYP2C19, 2D6, and 3A4) and increased the berberine plasma exposure. Therefore, a mixed micelle formulation strategy with P85 and tween 80 for drugs with high intestinal first-pass effects could be applied to increase the oral absorption and plasma concentrations of the drugs.

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4 Slow-drop infusion versus oral administration of citalopram: Comparison of plasma concentrations of the enantiomers of citalopram and its metabolites

10.1055/s-0040-1710112 ◽

2020 ◽

Author(s):

P Baumann ◽

R Nil

Keyword(s):

Oral Administration ◽

Plasma Concentrations

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Molecular docking studies of tea (Thea sinensis Linn.) polyphenols inhibition pattern with Rat P-glycoprotein

Physical Sciences Reviews ◽

10.1515/psr-2018-0165 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Babar Ali ◽

Qazi Mohammad Sajid Jamal ◽

Showkat R. Mir ◽

Saiba Shams ◽

Mohammad Amjad Kamal

Keyword(s):

Amino Acids ◽

Molecular Docking ◽

Binding Energy ◽

Oral Administration ◽

Docking Studies ◽

Vital Role ◽

Glycoprotein P ◽

High Affinity ◽

P Glycoprotein ◽

Inhibition Pattern

AbstractSince 3000 B.C., evergreen plant Thea sinensis (Theaceae) is used both as a social and medicinal beverage. Leaves of T. sinensis contain amino acids, vitamins, caffeine, polysaccharides and polyphenols. Most of the natural medicinal actions of tea are due to the availability and abundance of polyphenols mainly catechins. It has also been stated that some catechins were absorbed more rapidly than other compounds after the oral administration of tea and could increase the bio-enhancing activities of anticancer drugs by inhibiting P-glycoprotein (P-gp). The results of the molecular docking showed that polyphenols bind easily to the active P-gp site. All compounds exhibited fluctuating binding affinity ranged from −11.67 to −8.36 kcal/mol. Observed binding energy required for theaflavin to bind to P-gp was lowest (−11.67 kcal/mol). The obtained data that supports all the selected polyphenols inhibited P-gp and therefore may enhance the bioavailability of drugs. This study may play a vital role in finding hotspots in P-gp and eventually may be proved useful in designing compounds with high affinity and specificity to the protein.

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Plasma profile of cimicoxib in sheep after oral administration at two different rates

Polish Journal of Veterinary Sciences ◽

10.1515/pjvs-2017-0065 ◽

2017 ◽

Vol 20 (3) ◽

pp. 535-538

Author(s):

A. Di Salvo ◽

M. Giorgi ◽

H.K. Lee ◽

C. Vercelli ◽

F. Rueca ◽

...

Keyword(s):

Oral Administration ◽

Oral Treatment ◽

Plasma Concentrations ◽

Individual Variability ◽

Maximum Plasma ◽

Dose Rates ◽

Single Oral Administration ◽

Concentration Peak ◽

Value Range ◽

Slow Absorption

Abstract Sheep are often subjected to painful procedures and thus they need to be treated with analgesics. Nevertheless, knowledges about pharmacokinetic features of these drugs in this species are poor. The aim of this study was to evaluate plasma behaviour of cimicoxib in sheep after a single oral administration at two different dose rates (4 and 6 mg/kg). Maximum plasma concentrations of cimicoxib were equal to 273.78 (median value; range 189.00-567.32) and 565.01 (range 308.27-822.59) ng/mL after treatment with 4 and 6 mg/kg, respectively. The time of maximum concentration (Tmax) was achieved between 4 and 10 hours following treatment at the lower dose, and between 6 and 10 hours after the administration of the higher dose, with one sheep achieving the concentration peak at 0.75 hours. The slow absorption and the great individual variability in plasma concentration, probably due to ruminal effects, suggest that cimicoxib is not suitable for oral treatment in sheep.

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Neuroprotective Effect of Angelica Gigas Root in a Mouse Model of Ischemic Brain Injury through MAPK Signaling Pathway Regulation

10.21203/rs.3.rs-39355/v1 ◽

2020 ◽

Author(s):

Se-Eun Lee ◽

Jung-Hoon Kim ◽

Chiyeon Lim ◽

Suin Cho

Keyword(s):

Oral Administration ◽

Morphological Changes ◽

Neuroprotective Effect ◽

Plasma Concentrations ◽

Neuronal Cell ◽

Mapk Signaling ◽

Cresyl Violet ◽

Potential Candidate ◽

Angelica Gigas ◽

Brain Tissues

Abstract Background: The root of Angelica gigas Nakai (Apiaceae) has been traditionally used as an important herbal medicine to treat blood-deficiency-related disorders in Eastern Asian countries, and recently, it has been recognized as a potential candidate for improving cardiovascular diseases. Methods: In this study, the neuroprotective effect of a methanol extract of A. gigas root (RAGE) was investigated in a mouse stroke model induced by a 90 min transient middle cerebral artery occlusion (tMCAO). Infarction volumes and morphological changes in brain tissues were measured using TTC, cresyl violet, and H&E staining. The neuroprotective mechanism of RAGE was elucidated through investigation of protein expression levels using western blotting, IHC, and ELISA assays. The plasma concentrations of decursin, a major compound in RAGE, were measured after oral administration of RAGE to SD rats. Results: The infarction volumes in brain tissues were significantly reduced and the morphological deteriorations in the brain neuron cells were improved in tMCAO mice when pre-treated with RAGE at 1,000 mg/(kg bw·d) for two consecutive days. The neuroprotective mechanism of RAGE was confirmed to attenuate ERK-related MAPK signaling pathways in the ipsilateral hippocampus hemisphere in mice. The concentrations of decursin in rat plasma samples showed peak absorption and elimination in vivo after oral administration of RAGE at 100 mg/rat.Conclusion: Mice administered RAGE before the tMCAO operation had less neuronal cell death than those that were not administered RAGE prior to the operation, and this study provides preclinical evidence for use of A. gigas in ischemic stroke.

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Influence of Diet on Plasma Concentrations of Nifedipine Sustained-Release Granules after Oral Administration.

Japanese Journal of Hospital Pharmacy ◽

10.5649/jjphcs1975.18.605 ◽

1992 ◽

Vol 18 (6) ◽

pp. 605-611

Author(s):

DAN KOKUBU ◽

AKIHITO TAHARA ◽

HIDEKI MORI ◽

MASASHI TAKAHASHI ◽

ATSUMU NAKAYAMA ◽

...

Keyword(s):

Sustained Release ◽

Oral Administration ◽

Plasma Concentrations

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Pharmacokinetics of Doxycycline in Adults with Cystic Fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05710-11 ◽

2011 ◽

Vol 56 (1) ◽

pp. 70-74 ◽

Cited By ~ 32

Author(s):

Paul M. Beringer ◽

Heather Owens ◽

Albert Nguyen ◽

Debbie Benitez ◽

Adupa Rao ◽

...

Keyword(s):

Cystic Fibrosis ◽

Oral Administration ◽

Maximum Concentration ◽

Airway Remodeling ◽

Plasma Concentrations ◽

Compartment Model ◽

Time Curve ◽

Elimination Half ◽

Dose Oral

ABSTRACTCystic fibrosis (CF) is characterized by a chronic neutrophilic inflammatory response resulting in airway remodeling and progressive loss of lung function. Doxycycline is a tetracycline antibiotic that inhibits matrix metalloproteinase 9, a protease known to be associated with the severity of lung disease in CF. The pharmacokinetics of doxycycline was investigated during the course of a clinical trial to evaluate the short-term efficacy and safety in adults with CF. Plasma samples were obtained from 14 patients following a single intravenous dose and after 2 and 4 weeks of oral administration of doses ranging from 40 to 200 mg daily. The data were analyzed using noncompartmental and compartmental pharmacokinetics. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to infinity (AUC0-∞) values ranged from 1.0 to 3.16 mg/liter and 15.2 to 47.8 mg/liter × h, respectively, following single intravenous doses of 40 to 200 mg.Cmaxand time to maximum concentration of drug in serum (Tmax) values following multiple-dose oral administration ranged from 1.15 to 3.04 mg/liter and 1.50 to 2.33 h, respectively, on day 14 and 1.48 to 3.57 mg/liter and 1.00 to 2.17 on day 28. Predose sputum/plasma concentration ratios on days 14 and 28 ranged from 0.33 to 1.1 (mean, 0.71 ± 0.33), indicating moderate pulmonary penetration. A 2-compartment model best described the combined intravenous and oral data. Absorption was slow and delayed (absorption rate constant [Ka], 0.414 h−1; lag time, 0.484 h) but complete (bioavailability [F], 1.16). The distribution and elimination half-lives were 0.557 and 18.1 h, respectively. Based on these data, the plasma concentrations at the highest dose, 200 mg/day, are in the range reported to produce anti-inflammatory effectsin vivoand should be evaluated in clinical trials.

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HMG-CoA reductase inhibitors (Statins) and their Drug Interactions involving CYP enzymes, P-glycoprotein and OATP Transporters - An Overview

Current Drug Metabolism ◽

10.2174/1389200222666210114122729 ◽

2021 ◽

Vol 22 ◽

Author(s):

Rajkapoor Balasubramanian ◽

Naina Mohamed Pakkir Maideen

Keyword(s):

Drug Interactions ◽

Plasma Concentrations ◽

Cochrane Library ◽

Hmg Coa Reductase ◽

Cyp Enzymes ◽

Reductase Inhibitors ◽

P Glycoprotein ◽

Elevated Liver Enzymes ◽

Hmg Coa Reductase Inhibitors ◽

Coa Reductase

Background: Hydroxymethyl glutaryl-CoA (HMG-CoA) reductase inhibitors (Statins) are used to treat dyslipidemia. Generally, the statins are the substrates of CYP enzymes, P-glycoprotein (P-gp), and organic anion transporting polypeptides transporters (OATP1B1). Objective: This review article focuses on the clinical significance of statins, and their interactions in real practice. Method: The databases like Medline/PubMed Central/PubMed, Google Scholar, Science Direct, Cochrane Library, Directory of open access journals (DOAJ), and reference lists were searched to identify relevant articles. Results: Most of the drug interactions of statins result in elevated plasma concentrations and toxicity of statins due to the inhibition of CYP3A4, P-gp and/or OATP1B1 transporters. The toxicity of statins includes myopathy, rhabdomyolysis, elevated liver enzymes, acute kidney injury, and diabetes. The statins like Simvastatin, Lovastatin, and Atorvastatin are substrates of CYP3A4 enzyme and P-glycoprotein and their concomitant use with the drugs inhibiting or inducing them would result in changes in plasma concentrations and toxicity/efficacy. However, the statins like Pravastatin, Rosuvastatin and Pitavastatin are not substrates of CYP enzymes and hence the concomitant use of CYP inhibitors or inducers do not affect them. Almost all the statins are the substrates of OATP1B1 transporter, and the co-prescription of inhibitors of OATP1B1 elevates the plasma concentrations and muscle toxicity of statins. Conclusion: Understanding the interacting potential of each statin will enable the prescribers, pharmacists, and other health care professionals to use statins effectively without compromising patient safety.

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Clopidogrel

Fibrinolytic and Antithrombotic Therapy ◽

10.1093/oso/9780195155648.003.0013 ◽

2006 ◽

Author(s):

Richard C. Becker ◽

Frederick A. Spencer

Keyword(s):

Steady State ◽

Oral Dose ◽

Oral Administration ◽

Randomized Clinical Trials ◽

Peak Plasma ◽

Parent Compound ◽

Plasma Concentrations ◽

Significant Inhibition ◽

Inhibiting Effect ◽

Dependent Inhibition

Clopidogrel, a thienopyridine derivative, is a novel platelet antagonist that is several times more potent than ticlopidine but associated with fewer adverse effects. After repeated 75-mg oral doses of clopidogrel, plasma concentrations of the parent compound, which has no platelet-inhibiting effect, are very low. Clopidogrel is extensively metabolized in the liver. The main circulating metabolite is a carboxylic acid derivative with a plasma elimination half-life of 7.7 ± 2.3 hours. Approximately 50% of an oral dose is excreted in the urine and the remaining 50% in feces over the following 5 days. Dose-dependent inhibition of platelet aggregation is observed 2 hours after a single oral dose of clopidogrel, with a more significant inhibition achieved with loading doses (≥300 mg) by approximately 6 hours. Repeated doses of 75 mg of clopidogrel per day inhibit adenosine diphosphate (ADP)-mediated aggregation, with steady state being reached between day 3 and day 7. At steady state, the average inhibition to ADP is between 40% and 60%. Based on ex vivo studies, clopidogrel is approximately 100-fold more potent than ticlopidine. There are no cumulative antiplatelet effects with prolonged oral administration. The combined administration of clopidogrel (300 mg loading dose) and aspirin yields a readily discernible platelet-inhibiting effect within 90 to 120 minutes. Clopidogrel selectively inhibits the binding of ADP to its platelet receptor (P2Y12) and the subsequent G-protein–linked mobilization of intracellular calcium and activation of the glycoprotein (GP)IIb/IIIa complex (Gachet et al., 1992). The specific receptor has been cloned and is abundantly present on the platelet surface (Hollopter et al., 2001). Clopidogrel has no direct effect on cyclooxygenase, phosphodiesterase, or adenosine uptake. Clopidogrel is rapidly absorbed following oral administration with peak plasma levels of the predominant circulating metabolite occurring approximately 60 minutes later. Administration with meals does not significantly modify the bioavailability of clopidogrel. The available information suggests that clopidogrel offers safety advantages over ticlopidine, particularly with regard to bone marrow suppression and other hematologic abnormalities. Although thrombotic thrombocytopenic purpura (TTP) has been reported with clopidogrel (Bennett et al., 2000), its occurrence (11 cases per 3 million patients treated) is rare, and has not been reported in randomized clinical trials performed to date.

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