scholarly journals Enhanced Intestinal Absorption and Pharmacokinetic Modulation of Berberine and Its Metabolites through the Inhibition of P-Glycoprotein and Intestinal Metabolism in Rats Using a Berberine Mixed Micelle Formulation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 882
Author(s):  
Mihwa Kwon ◽  
Dong Yu Lim ◽  
Chul Haeng Lee ◽  
Ji-Hyeon Jeon ◽  
Min-Koo Choi ◽  
...  
Keyword(s):  
Oral Administration ◽  
Intestinal Absorption ◽  
Mixed Micelle ◽  
Oral Absorption ◽  
Plasma Concentrations ◽  
Tween 80 ◽  
Rat Plasma ◽  
Intestinal Metabolism ◽  
Plasma Exposure ◽  
P Glycoprotein

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.

scholarly journals Simultaneous Determination and Pharmacokinetic Characterization of Glycyrrhizin, Isoliquiritigenin, Liquiritigenin, and Liquiritin in Rat Plasma Following Oral Administration of Glycyrrhizae Radix Extract

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1816 ◽  
Author(s):  
You Jin Han ◽  
Bitna Kang ◽  
Eun-Ju Yang ◽  
Min-Koo Choi ◽  
Im-Sook Song
Keyword(s):  
Oral Administration ◽  
Analytical Method ◽  
Plasma Concentrations ◽  
Rat Plasma ◽  
Pharmacokinetic Studies ◽  
Elution Time ◽  
Glycyrrhizae Radix ◽  
Single Oral Administration ◽  
Limit Of Quantitation ◽  
Liquid Chromatography Tandem Mass

Glycyrrhizae Radix is widely used as herbal medicine and is effective against inflammation, various cancers, and digestive disorders. We aimed to develop a sensitive and simultaneous analytical method for detecting glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin, the four marker components of Glycyrrhizae Radix extract (GRE), in rat plasma using liquid chromatography-tandem mass spectrometry and to apply this analytical method to pharmacokinetic studies. Retention times for glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin were 7.8 min, 4.1 min, 3.1 min, and 2.0 min, respectively, suggesting that the four analytes were well separated without any interfering peaks around the peak elution time. The lower limit of quantitation was 2 ng/mL for glycyrrhizin and 0.2 ng/mL for isoliquiritigenin, liquiritigenin, and liquiritin; the inter- and intra-day accuracy, precision, and stability were less than 15%. Plasma concentrations of glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin were quantified for 24 h after a single oral administration of 1 g/kg GRE to four rats. Among the four components, plasma concentration of glycyrrhizin was the highest and exhibited a long half-life (23.1 ± 15.5 h). Interestingly, plasma concentrations of isoliquiritigenin and liquiritigenin were restored to the initial concentration at 4–10 h after the GRE administration, as evidenced by liquiritin biotransformation into isoliquiritigenin and liquiritigenin, catalyzed by fecal lysate and gut wall enzymes. In conclusion, our analytical method developed for detecting glycyrrhizin, isoliquiritigenin, liquiritigenin, and liquiritin could be successfully applied to investigate their pharmacokinetic properties in rats and would be useful for conducting further studies on the efficacy, toxicity, and biopharmaceutics of GREs and their marker components.

Bifidobacterium breve MCC1274 with glycosidic activity enhances in vivo isoflavone bioavailability

2019 ◽  
Vol 10 (5) ◽  
pp. 521-531 ◽  
Author(s):  
R. Yao ◽  
C.B. Wong ◽  
K. Nakamura ◽  
E. Mitsuyama ◽  
A. Tanaka ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Gut Microbiota ◽  
Oral Administration ◽  
Kinetic Analysis ◽  
Intestinal Absorption ◽  
Relative Abundance ◽  
Intestinal Metabolism ◽  
Control Groups ◽  
Bifidobacterium Breve

Polyphenols are plant derived compounds that exert many beneficial health effects to the human host. However, associated health benefits of dietary polyphenol are highly dependent on their intestinal metabolism, bioavailability, and absorption. Bifidobacteria, which represent the key members of gut microbiota, have been suggested to promote gut microbial homeostasis and may be involved in the metabolism of polyphenols. In this study, the capabilities of thirteen Bifidobacterium strains in hydrolysing polyphenol glycosides were evaluated. Among the tested strains, Bifidobacterium breve MCC1274 was found to possess the highest β-glucosidase activity and strong capability to convert daidzin and trans-polydatin to their aglycones; while kinetic analysis revealed that B. breve MCC1274 hydrolysed more than 50% of daidzin and trans-polydatin at less than 3 h of incubation. Further investigation using rats with an antibiotics-disturbed microbiome revealed that following the ingestion of daidzin glycoside, oral administration of B. breve MCC1274 significantly enhanced the plasma concentration of daidzein in rats pre-treated with antibiotics as compared to antibiotics-pre-treated control and non-treated control groups. The relative abundance of Actinobacteria and the total numbers of B. breve were also significantly higher in antibiotics-pre-treated rats administered with B. breve MCC1274 than that of the control groups. These findings suggest that B. breve MCC1274 is effective in enhancing the bioavailability of daidzein in the gut under dysbiosis conditions and may potentially improve intestinal absorption of isoflavones and promote human health.

scholarly journals An UPLC-MS/MS Method for Simultaneous Quantification of the Components of Shenyanyihao Oral Solution in Rat Plasma

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Chunbo Jiang ◽  
Guoqiang Liang ◽  
Yan Ren ◽  
Tianjun Xu ◽  
Yongliang Song ◽  
...  
Keyword(s):  
Oral Administration ◽  
Ferulic Acid ◽  
Protocatechuic Acid ◽  
Plasma Sample ◽  
Plasma Concentrations ◽  
Rat Plasma ◽  
Oral Solution ◽  
Pharmacokinetic Parameters ◽  
Simultaneous Quantification ◽  
Chronic Nephritis

Objectives. To study the quantification of the components in rat plasma after oral administration of Shenyanyihao oral solution. Methods. Shenyanyihao oral solution has been traditionally used for the treatments of chronic nephritis in clinics. Stachydrine, Danshensu, chlorogenic acid, protocatechuic acid, plantamajoside, aesculetin, isoquercitrin, ferulic acid, baicalin, and baicalein are regarded as the main compounds in Shenyanyihao oral solution. A sensitive, efficient, and precise UPLC-MS/MS method was established and validated for the quantification of the components in rat plasma after oral administration of Shenyanyihao oral solution. Results. The main pharmacokinetic parameters of the components were acquired based on the analysis of the plasma sample by a noncompartmental method using the WinNonlin7.0 pharmacokinetic program. Danshensu, protocatechuic acid, isoquercitrin, and ferulic acid from Shenyanyihao oral solution were quickly absorbed, and their peak concentration occurred at less than 0.5 h. The pharmacokinetic parameter of the average t1/2 from Danshensu was 3.91 h in rats, and it was the most rapid distribution and elimination among the components. In addition, the Cmax of stachydrine and baicalin were revealed as the higher plasma concentrations in rats. Conclusions. This pharmacokinetic study seems to be useful for a further clinical study of Shenyanyihao oral solution in the treatments of chronic nephritis.

scholarly journals Identification and Pharmacokinetic Studies on Complanatuside and Its Major Metabolites in Rats by UHPLC-Q-TOF-MS/MS and LC-MS/MS

Molecules ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. 71 ◽  
Author(s):  
Yu-Feng Yao ◽  
Chao-Zhan Lin ◽  
Fang-Le Liu ◽  
Run-Jing Zhang ◽  
Qiu-Yu Zhang ◽  
...  
Keyword(s):  
Oral Administration ◽  
Degradation Products ◽  
Plasma Concentrations ◽  
Rat Plasma ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Studies ◽  
Maximum Plasma ◽  
Time Curve ◽  
Tof Ms

The metabolic and pharmacokinetic studies on complanatuside, a quality marker of a Chinese materia medicatonic, Semen Astragali Complanati, were carried out. The UHPLC-Q-TOF/MS (ultra-high performance liquid chromatography coupled with electrospray ionization tandem quadrupole-time-of-flight mass spectrometry) method was applied to identify the metabolites of complanatuside in rat plasma, bile, stool, and urine after oral administration at the dosage of 72 mg/kg. Up to 34 metabolites (parent, 2 metabolites of the parent drug, and 31 metabolites of the degradation products) were observed, including processes of demethylation, hydroxylation, glucuronidation, sulfonation, and dehydration. The results indicated glucuronidation and sulfonation as major metabolic pathways of complanatuside in vivo. Meanwhile, a HPLC-MS method to quantify complanatuside and its two major metabolites—rhamnocitrin 3-O-β-glc and rhamnocitrin—in rat plasma for the pharmacokinetic analysis was developed and validated. The Tmax (time to reach the maximum drug concentration) of the above three compounds were 1 h, 3 h, and 5.3 h, respectively, while the Cmax (maximum plasma concentrations)were 119.15 ng/mL, 111.64 ng/mL, and 1122.18 ng/mL, and AUC(0-t) (area under the plasma concentration-time curve) was 143.52 µg/L·h, 381.73 µg/L·h, and 6540.14 µg/L·h, accordingly. The pharmacokinetic characteristics of complanatuside and its two metabolites suggested that complanatuside rapidly metabolized in vivo, while its metabolites—rhamnocitrin—was the main existent form in rat plasma after oral administration. The results of intracorporal processes, existing forms, and pharmacokinetic characteristics of complanatuside in rats supported its low bioavailability.

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

2008 ◽  
Vol 36 (5) ◽  
pp. 807-810 ◽  
Author(s):  
Yoshiaki Kitamura ◽  
Hisao Koto ◽  
Shinobu Matsuura ◽  
Takeshi Kawabata ◽  
Hiroshi Tsuchiya ◽  
...  
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
P Glycoprotein ◽  
Modest Effect

scholarly journals Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2948 ◽  
Author(s):  
Sowon Lee ◽  
Mihwa Kwon ◽  
Min-Koo Choi ◽  
Im-Sook Song
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Repeated Administration ◽  
Rat Plasma ◽  
Control Group ◽  
Red Ginseng ◽  
Ginseng Extract ◽  
Protein Levels ◽  
Liquid Chromatography Tandem Mass ◽  
Dosing Regimens

We aimed to investigate the effects of red ginseng extract (RGE) on the expression of efflux transporters and to study the pharmacokinetics of representative substrate. For this, rats received single or repeated administration of RGE (1.5 g/kg/day) for 1 and 2 weeks via oral gavage. mRNA and protein levels of multidrug resistance-associated protein2 (Mrp2), bile salt export pump (Bsep), and P-glycoprotein (P-gp) in the rat liver were measured via real-time polymerase chain reaction and Western blot analysis. Ginsenosides concentrations from the rat plasma were also monitored using a liquid chromatography–tandem mass spectrometry (LC–MS/MS) system. Plasma concentrations of ginsenoside Rb1, Rb2, Rc, and Rd following repeated administration of RGE for 1 and 2 weeks were comparable but significantly higher than those after single administration of RGE. These dosing regimens did not induce significant biochemical abnormalities in the liver, kidneys, and lipid homeostasis. In the RGE repeated oral administration groups, the mRNA and protein levels of Mrp2 significantly decreased. Accordingly, we investigated the changes in the pharmacokinetics of methotrexate, a probe substrate for Mrp2, following intravenous administration of 3 mg/kg methotrexate to rats in the RGE 1-week repeated oral administration group, compared to that in the control group. Biliary excretion, but not urinary excretion, of methotrexate decreased in the RGE repeated administration group, compared to that in the control group. Consequently, the plasma concentrations of methotrexate slightly increased in the RGE repeated administration group. In conclusion, repeated administration of RGE for 1 week resulted in a decrease in Mrp2 expression without inducing significant liver or kidney damage. Pharmacokinetic herb–drug interaction between RGE and methotrexate might occur owing to the decrease in the mRNA and protein levels of Mrp2.

scholarly journals Investigation of the Functional Role of P-Glycoprotein in Limiting the Oral Bioavailability of Lumefantrine

2013 ◽  
Vol 58 (1) ◽  
pp. 489-494 ◽  
Author(s):  
Wahajuddin ◽  
Kanumuri S. R. Raju ◽  
Sheelendra P. Singh ◽  
Isha Taneja
Keyword(s):  
Intestinal Absorption ◽  
Oral Absorption ◽  
Stability Study ◽  
Cytochrome P450 3A ◽  
Glycoprotein P ◽  
Active Efflux ◽  
P Glycoprotein

ABSTRACTIn the quest to explore the reason for the low and variable bioavailability of lumefantrine, we investigated the possible role of P-glycoprotein (P-gp) in lumefantrine intestinal absorption. Anin situsingle-pass intestinal perfusion study in rats with the P-gp inhibitor verapamil or quinidine and an ATPase assay with human P-gp membranes indicated that lumefantrine is a substrate of P-gp which limits its intestinal absorption. To confirm these findings, anin vivopharmacokinetic study was performed in rats. The oral administration of verapamil (10 mg/kg of body weight) along with lumefantrine caused a significant increase in its bioavailability with a concomitant decrease in clearance. The increase in bioavailability of lumefantrine could be due to inhibition of P-gp and/or cytochrome P450 3A in the intestine/liver by verapamil. However, in a rat intestinal microsomal stability study, lumefantrine was found to be resistant to oxidative metabolism. Further, anin situpermeation study clearly showed a significant role of P-gp in limiting the oral absorption of lumefantrine. Thus, the increase in lumefantrine bioavailability with verapamil is attributed in part to the P-gp-inhibitory ability of verapamil. In conclusion, lumefantrine is a substrate of P-gp, and active efflux by P-gp across the intestine partly contributed to the low/variable bioavailability of lumefantrine.

scholarly journals Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats

Pharmaceutics ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 124 ◽  
Author(s):  
Zhi-Yuan Zhang ◽  
Hua Zhang ◽  
Dan Liu ◽  
Ying-Yuan Lu ◽  
Xin Wang ◽  
...  
Keyword(s):  
Oral Administration ◽  
Tissue Distribution ◽  
High Performance ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Pharmacokinetic Profile ◽  
Rat Plasma ◽  
Drug Candidate ◽  
Liquid Chromatography Tandem Mass

Methyl 3-amino-6-methoxythieno [2,3-b] quinoline-2-carboxylate (PU-48) is a novel diuretic urea transporter inhibitor. The aim of this study is to investigate the profile of plasma pharmacokinetics, tissue distribution, and excretion by oral dosing of PU-48 in rats. Concentrations of PU-48 within biological samples are determined using a validated high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. After oral administration of PU-48 (3, 6, and 12 mg/kg, respectively) in self-nanomicroemulsifying drug delivery system (SNEDDS) formulation, the peak plasma concentrations (Cmax), and the area under the curve (AUC0–∞) were increased by the dose-dependent and linear manner, but the marked different of plasma half-life (t1/2) were not observed. This suggests that the pharmacokinetic profile of PU-48 prototype was first-order elimination kinetic characteristics within the oral three doses range in rat plasma. Moreover, the prototype of PU-48 was rapidly and extensively distributed into thirteen tissues, especially higher concentrations were detected in stomach, intestine, liver, kidney, and bladder. The total accumulative excretion of PU-48 in the urine, feces, and bile was less than 2%. This research is the first report on disposition via oral administration of PU-48 in rats, and it provides important information for further development of PU-48 as a diuretic drug candidate.

scholarly journals Identification and pharmacokinetics of saponins in Rhizoma Anemarrhenae after oral administration to rats by HPLC-Q-TOF/MS and HPLC-MS/MS

2021 ◽  
Vol 71 (4) ◽  
pp. 567-585
Author(s):  
Hai-Qiao Wang ◽  
Fen Lan ◽  
Yi-Han Zhang ◽  
Jin-Er Xia ◽  
Xiao-Mei Gong ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Oral Administration ◽  
Pharmacokinetic Study ◽  
Matrix Effect ◽  
Plasma Concentrations ◽  
Rat Plasma ◽  
Bioactive Components ◽  
Elimination Half ◽  
Intended Use ◽  
Tof Ms

Abstract Rhizoma Anemarrhenae is a well-known herbal medicine with saponins as its commonly regarded major bioactive components. It is essential to classify the properties of saponins which are associated with their toxicity and efficacy. In this study, 25 compounds were identified by HPLC-Q-TOF/MS in the extract of Rhizoma Anemarrhenae and 8 saponins were detected in rat plasma by HPLC-MS/MS after oral administration of this extract. These were neomangiferin, mangiferin, timosaponin E1, timosaponin E, timosaponin B-II, timosaponin B-III, timosaponin A-III and timosaponin A-I. A sensitive and accurate HPLC-MS/MS method was developed and successfully applied to a pharmacokinetic study of the abovementioned eight saponins after oral administration of the Rhizoma Anemarrhenae extract to rats. The method validation, including specificity, linearity, precision, accuracy, recovery, matrix effect and robustness, met the requirements of the intended use. The pharmacokinetic parameter, T max value, ranged from 2 to 8 h for these eight saponins whereas their elimination half-life (t 1/2) ranged from 4.06 to 9.77 h, indicating slow excretion. The plasma concentrations of these eight saponins were all very low, indicating a relatively low oral bioavailability. All these results provide support for further clinical studies.

scholarly journals Effects of lα-hydroxylated metabolites of cholecalciferol on intestinal radiocalcium absorption in goats

1984 ◽  
Vol 51 (1) ◽  
pp. 157-164 ◽  
Author(s):  
Knut Hove
Keyword(s):  
Fatty Acid ◽  
Oral Administration ◽  
Intestinal Absorption ◽  
Plasma Concentrations ◽  
Rumen Degradation ◽  
Hydroxylated Metabolites ◽  
Naturally Occurring ◽  
Isotope Technique ◽  
Dose Dependent ◽  
Double Isotope

1. Intestinal absorption of 47Ca was measured by a double-isotope technique in goats treated with 1, 5 or 25 μg of 1,25-dihydroxycholecalciferol (1,25(OH)2D3). The effects of giving 1,25(OH)2D3 by intravenous (iv) infusion for 30–36 h were compared at each dose level with the effects obtained by oral administration of 1,25(OH)2D3 either in ethanol or protected against rumen degradation in fatty acid pellets.2. Dose-dependent increments in absorption followed the treatments, with a doubling of absorption at the 1 μg dose and three- to fivefold increases with the 5 and 25 μg doses. 47Ca absorption was equally stimulated 2 and 6 d after treatment but had returned to pretreatment levels 12–14 d after treatment.3. Intravenous and protected oral administration of 1,25(OH)2D3 stimulated 47Ca absorption to the same extent, in spite of two- to fivefold higher plasma concentrations of 1,25(OH)2D3 after iv treatment. Somewhat lower increments in 47Ca absorption were seen using ethanol as the vehicle for oral administration.4. The naturally occurring metabolites 1,24(R),25-trihydroxycholecalciferol and 1,25(S),26-trihydroxy-cholecalciferol had only one-tenth to one-fifteenth the potency of 1,25(OH)2D3 in stimulating 47Ca absorption, while synthetic lα-hydroxycholecalciferol appeared to be twice as effective as 1,25(OH)2D3 when tested at a high (10μg) dose.

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