Limited oral bioavailability and potential non-linear pharmacokinetics of piperine in Sprague-Dawley rats

Background: Timosaponin A-III is one of the most promising active saponins from Anemarrhena asphodeloides Bge. As an oral chemotherapeutic agent, there is an urgent need to clarify its biopharmaceutics and pharmacokinetics to improve its development potential. Objective: This research explores the bioavailability of timosaponin A-III and clarifies its absorption and metabolism mechanisms by a sensitive and specific HPLC-MS/MS method. Methods: Pharmacokinetics and bioavailability studies of timosaponin A-III were performed in Sprague-Dawley rats by oral (20 g/kg) and intravenous administration (2 mg/kg). Control group was given the same volume of normal saline. The absorption of timosaponin A-III was investigated in a rat intestinal perfusion model in situ and a Caco-2 cell transport model in vitro. The metabolic rate of timosaponin A-III was determined in a rat liver microsome incubation system. Results: After the oral administration, timosaponin A-III reached Cmax of 120.90 ± 24.97 ng/mL at 8 h, and the t1/2 was 9.94 h. The absolute oral bioavailability of timosaponin A-III is 9.18%. The permeability coefficients of timosaponin A-III in four intestinal segments ranged from 4.98 to 5.42 cm/s, indicating a difficult absorption. A strikingly high transport of timosaponin A-III was found, PappBA 3.27 ± 0.64 × 10−6 cm/s, which was abolished by a P-gp inhibitor. Rat liver microsome incubation studies showed that timosaponin A-III could hardly be metabolized, with a t1/2 of over 12 h. In addition, the solubility test showed a low solubility in PBS solution, 30.58 μg/mL. Conclusion: Timosaponin A-III exhibited low oral bioavailability by oral and intravenous admiConclusion: nistration, which was probably caused by its low permeability and solubility. This study may provide a reference for the rational clinical use and further study on the pharmacology or toxicology of timosaponin A-III.

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Oral Bioavailability of Cyclotrimethylenetrinitramine (RDX) from Contaminated Site Soils in Rats

International Journal of Toxicology ◽

10.1080/10915810802366885 ◽

2008 ◽

Vol 27 (4) ◽

pp. 317-322 ◽

Cited By ~ 3

Author(s):

Lee C. B. Crouse ◽

Mark W. Michie ◽

Michael A. Major ◽

Glenn J. Leach ◽

Gunda Reddy

Keyword(s):

Contaminated Soil ◽

Contaminated Soils ◽

Oral Bioavailability ◽

Risk Assessments ◽

Contaminated Site ◽

Blood Levels ◽

Sprague Dawley ◽

Peak Absorption ◽

Sprague Dawley Rats ◽

Soil And Water

Cyclotrimethylenetrinitramine (RDX), a commonly used military explosive, was detected as a contaminant of soil and water at Army facilities and ranges. This study was conducted to determine the relative oral bioavailability of RDX in contaminated soil and to develop a method to derive bioavailability adjustments for risk assessments using rodents. Adult male Sprague-Dawley rats preimplanted with femoral artery catheters were dosed orally with gelatin capsules containing either pure RDX or an equivalent amount of RDX in contaminated soils from Louisiana Army Ammunition Plant (LAAP) (2300 μg/g of soil) or Fort Meade (FM) (670 μg/g of soil). After dosing rats, blood samples were collected from catheters at 2-h intervals (2, 4, 6, 8, 10, and 12) and at 24 and 48 h. RDX levels in the blood were determined by gas chromatography. The results show that the peak absorption of RDX in blood was 6 h for neat RDX (1.24 mg/kg) and for RDX from contaminated soil (1.24 mg/kg) of LAAP. Rats dosed with RDX-contaminated FM soil (0.2 mg/kg) showed peak levels of RDX in blood at 6 h, whereas their counterparts that received an identical dose (0.2 mg/kg) of neat RDX showed peak absorption at 4 h. The blood levels of absorbed RDX from LAAP soil were about 25% less than for neat RDX, whereas the bioavailability of RDX from FM soils was about 15% less than that seen in rats treated with neat RDX (0.2 mg/kg). The oral bioavailability in rats fed RDX in LAAP soil and the FM soil was reduced with the neat compound but decrease in bioavailability varied with the soil type.

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Preclinical pharmacokinetic evaluation of resveratrol trimethyl ether in sprague-dawley rats: the impacts of aqueous solubility, dose escalation, food and repeated dosing on oral bioavailability

Journal of Pharmaceutical Sciences ◽

10.1002/jps.22588 ◽

2011 ◽

Vol 100 (10) ◽

pp. 4491-4500 ◽

Cited By ~ 29

Author(s):

Hai-shu Lin ◽

Paul C. Ho

Keyword(s):

Dose Escalation ◽

Oral Bioavailability ◽

Aqueous Solubility ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Trimethyl Ether ◽

Repeated Dosing ◽

Pharmacokinetic Evaluation

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Polysorbate 20 alters the oral bioavailability of etoposide in wild type and mdr1a deficient Sprague-Dawley rats

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2018.04.006 ◽

2018 ◽

Vol 543 (1-2) ◽

pp. 352-360 ◽

Cited By ~ 14

Author(s):

Ahmed A. Abdulhussein Al-Ali ◽

Jeffrey Rong Chao Quach ◽

Christoffer Bundgaard ◽

Bente Steffansen ◽

René Holm ◽

...

Keyword(s):

Oral Bioavailability ◽

Wild Type ◽

Sprague Dawley ◽

Polysorbate 20 ◽

Sprague Dawley Rats

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Bioactive Markers Based Pharmacokinetic Evaluation of Extracts of a Traditional Medicinal Plant,Piper sarmentosum

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nep143 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Khalid Hussain ◽

Zhari Ismail ◽

Amirin Sadikun ◽

Pazillah Ibrahim

Keyword(s):

Oral Bioavailability ◽

High Performance ◽

Ethanol Extract ◽

Intestinal Wall ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Human Pharmacokinetics ◽

Sprague Dawley ◽

Sprague Dawley Rats

In vitroassays are economical and easy to perform but to establish relevance of their results to real clinical outcome in animals or human, pharmacokinetics is prerequisite. Despite variousin vitropharmacological activities of extracts ofPiper sarmentosum, there is no report of pharmacokinetics. Therefore, the present study aimed to evaluate ethanol extract of fruit of the plant in dose of 500 mg kg−1orally for pharmacokinetics. Sprague-Dawley rats were randomly divided into groups 1, 2, and 3 (eachn= 6) to study absorption, distribution and excretion, respectively. High performance liquid chromatography (HPLC) with ultraviolet detection was applied to quantify pellitorine, sarmentine and sarmentosine in plasma, tissues, feces and urine to calculate pharmacokinetic parameters. Pellitorine exhibited maximum plasma concentration (Cmax) 34.77 ng mL−1± 1.040, time to achieveCmax(Tmax) 8 h, mean resident time (MRT) 26.00 ± 0.149 h and half life (t1/2) 18.64 ± 1.65 h. Sarmentine showedCmax191.50 ± 12.69 ng mL−1,Tmax6 h, MRT 11.12 ± 0.44 h andt1/210.30 ± 1.98 h. Sarmentosine exhibited zero oral bioavailability because it was neither detected in plasma nor in tissues, and in urine. Pellitorine was found to be distributed in intestinal wall, liver, lungs, kidney, and heart, whereas sarmentine was found only in intestinal wall and heart. The cumulative excretion of pellitorine, sarmentine and sarmentosine in feces in 72 h was 0.0773, 0.976, and 0.438 μg, respectively. This study shows that pellitorine and sarmentine have good oral bioavailability while sarmentosine is not absorbed from the gastrointestinal tract.

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