The Absolute Bioavailability and Dose Proportionality of Intravenous and Oral Dosage Regimens of Recainam

Erinacine S, so far known to have been produced only in Hericium erinaceus mycelia, has just recently been discovered and is able to reduce amyloid plaque growth and improve neurogenesis in aged brain of rats. However, few investigations have been conducted on the absorption, distribution, and excretion study of Erinacine S. This study aimed to investigate the absolute bioavailability, tissue distribution, and excretion of Erinacine S in H. Erinaceus mycelia in eight-week old Sprague-Dawley rats. After oral administration and intravenous administration of 2.395 g/kg body weight of the H. erinaceus mycelia extract (equivalent to 50 mg/kg body weight Erinacine S) and 5 mg/kg of Erinacine S, respectively, the absolute bioavailability was estimated as 15.13%. In addition, Erinacine S was extensively distributed in organs such as brain, heart, lung, liver, kidney, stomach, small intestine, and large intestine. The maximum concentration of Erinacine S was observed in the stomach, 2 h after the oral administration of H. erinaceus mycelia extract, whereas the maximum amount of Erinacine S found in other tissues were seen after 8 h. Total amount of unconverted Erinacine S eliminated in feces and urine in 24 h was 0.1% of the oral dosage administrated. This study is the first to show that Erinacine S can penetrate the blood–brain barrier of rats and thus support the development of H. erinaceus mycelia, for the treatment of neurological diseases.

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Pharmacokinetics of rosmarinic acid in rats by LC-MS/MS: absolute bioavailability and dose proportionality

RSC Advances ◽

10.1039/c6ra28237g ◽

2017 ◽

Vol 7 (15) ◽

pp. 9057-9063 ◽

Cited By ~ 15

Author(s):

Jingxian Wang ◽

Guoyuan Li ◽

Tianqi Rui ◽

An Kang ◽

Guochun Li ◽

...

Keyword(s):

Rosmarinic Acid ◽

Dose Proportionality ◽

Absolute Bioavailability ◽

Rapid Absorption ◽

Pharmacokinetic Properties

The pharmacokinetic properties of RA were characterized as rapid absorption, middle-speed elimination, poor absolute bioavailability, and lack of dose proportionality.

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Study to investigate the absolute bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects

Clinical Pharmacology & Therapeutics ◽

10.1016/j.clpt.2003.11.085 ◽

2004 ◽

Vol 75 (2) ◽

pp. P22 ◽

Cited By ~ 8

Author(s):

S Stevenson

Keyword(s):

Oral Dose ◽

Single Oral Dose ◽

Absolute Bioavailability ◽

Healthy Male ◽

The Absolute ◽

Male Subjects

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5-Azacytidine increases HbF production and reduces anemia in sickle cell disease: dose-response analysis of subcutaneous and oral dosage regimens

Blood ◽

10.1182/blood.v66.3.527.527 ◽

1985 ◽

Vol 66 (3) ◽

pp. 527-532 ◽

Cited By ~ 36

Author(s):

GJ Dover ◽

S Charache ◽

SH Boyer ◽

G Vogelsang ◽

M Moyer

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Dose Response ◽

Initial Dose ◽

Fetal Hemoglobin ◽

Oral Dosage ◽

Response Analysis ◽

Cell Disease ◽

Dosage Regimens ◽

Galactokinase Activity

Abstract Varying doses of 5-azacytidine (5-aza) were given to four sickle cell individuals for 500, 200, 100, and 30 days. The percentage of fetal hemoglobin (HbF) containing reticulocytes (F reticulocytes) increased two- to five-fold within five days of 5-aza therapy in all patients, with a two- to three-fold rapid response (less than 48 hours after initial dose) in three patients. Reticulocyte suppression was not observed prior to, during, or after therapy in those patients who responded within 48 hours. Subcutaneous 5-aza was given in 35-day courses consisting of every day, every other day, or three consecutive days a week. No marrow toxicity was observed on any of the regimens. For three patients, the highest average F reticulocyte level was observed on the three consecutive day a week regimen. Oral 5-aza, given with tetrahydrouridine, produced comparable F reticulocyte response. In the two patients treated for more than 100 days, Hb levels increased to 11 to 12 and 9 g/dL, MCV and MCH increased by 25%, and lysate HbF levels peaked at 12% and 20%. Fetal erythroid characteristics (i- antigen, galactokinase activity, and G gamma/A gamma ratios) did not correlate with maximal HbF production. The frequency of vasoocclusive crises appeared to decrease in both patients followed for more than 100 days.

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Development of an Oral Dosage Form of Azacitidine: Overcoming Challenges in Chemistry, Formulation, and Bioavailability.

Blood ◽

10.1182/blood.v108.11.4850.4850 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4850-4850

Author(s):

Maxine L. Stoltz ◽

Jeffrey B. Etter ◽

Tanja Obradovic ◽

Richard Jia

Keyword(s):

Dose Escalation ◽

Bioanalytical Methods ◽

Enzymatic Degradation ◽

Dosage Form ◽

Oral Dosage ◽

Absolute Bioavailability ◽

Dose Escalation Study ◽

Oral Dosing ◽

Oral Dosage Form ◽

Highly Sensitive

Abstract Azacitidine (Vidaza®), an epigenetic modifier which exerts its therapeutic effect through gene demethylation, is currently approved in a subcutaneous (sc) dosage form for the treatment of myelodysplastic syndromes (MDS). Low-dose, chronic demethylation may lead to improved antiproliferative activity while minimizing side effects. Such chronic demethylation would require a convenient, more frequent dosing schedule. It has, therefore, been an objective of Pharmion Corporation to develop an oral dosage form of azacitidine that could improve the safety and efficacy attributes of the parenterally administered formulation plus have desirable pharmacokinetic characteristics. Azacitidine presents several significant challenges with respect to oral administration including sub-optimal physiochemical characteristics, hydrolytic instability, and active enzymatic degradation - all non-conducive to high passive intestinal tract absorption. Moreover, the drug requires formulated tablet strengths accommodating widely flexible treatment regimens yet must be formulated to avoid the chemical and enzymatic degradation occurring presystemically. Additionally, nonclinical testing of azacitidine bioavailability is hampered by inappropriate animal models representing human gastrointestinal tracts conditions, low tolerability of the drug in several animal species, widely variable pharmacokinetic behavior, and lack of highly sensitive bioanalytical methods for measuring the drug. Data on orally administered azacitidine are sparse but hint at some degree of bioavailability in mice where multiple oral dosing with the drug resulted in lower LD50 values than multiple dosing by the intravenous route (data on file at Pharmion). A published report following long term oral dosing (0.2 mg/kg/day of azacitidine plus 200 mg tetrahydrouridine 3 days per week) in a patient with sickle cell disease resulted in significant increases in total and fetal hemoglobin suggesting absorption of the drug followed by systemic effects (Dover, 1985). A study recently conducted in dogs given azacitidine orally (6 mg/kg) compared to sc and iv (2 mg/kg) showed the drug was absorbed rapidly by the oral route (Tmax, 15 min) with absolute bioavailability of 67% (compared to 71% following sc dosing). Additional in vitro and ex vivo characterization of azacitidine stability and permeability have been performed. Data from these studies have been utilized to develop a solid oral dosage form of azacitidine that will move forward into additional animal testing and clinical evaluation. Highly sensitive bioanalytical methods have also been developed for the quantitation of azacitidine in dog and human plasma. A single oral dose escalation study will be conducted in patients to assess the safety, tolerability, and pharmacokinetics of orally administered azacitidine. Data will be evaluated continuously during the dose escalation study. Information generated from these studies will be used to appropriately design a full oral azacitidine clinical development program.

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INVESTIGATION OF DOSE PROPORTIONALITY AND ABSOLUTE BIOAVAILABILITY OF BROFAROMINE IN HEALTHY VOLUNTEERS

Clinical Neuropharmacology ◽

10.1097/00002826-199202001-00835 ◽

1992 ◽

Vol 15 ◽

pp. 430B ◽

Cited By ~ 1

Author(s):

K. H. Antonin ◽

K. Kucher ◽

L. Fuchs ◽

P. R. Bieck ◽

E. Schmidt

Keyword(s):

Healthy Volunteers ◽

Dose Proportionality ◽

Absolute Bioavailability

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Artemisinin Pharmacokinetics and Efficacy in Uncomplicated-Malaria Patients Treated with Two Different Dosage Regimens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.4.1026-1031.2002 ◽

2002 ◽

Vol 46 (4) ◽

pp. 1026-1031 ◽

Cited By ~ 39

Author(s):

Toufigh Gordi ◽

Dinh Xuan Huong ◽

Trinh Ngoc Hai ◽

Nguyen Thi Nieu ◽

Michael Ashton

Keyword(s):

High Performance ◽

Parasite Clearance ◽

Oral Dosage ◽

Pharmacokinetic Parameters ◽

Oral Clearance ◽

Dosage Regimens ◽

Drug Concentrations ◽

Group A ◽

Group B ◽

Pass Metabolism

ABSTRACT The immediate efficacies of two oral dosage regimens of artemisinin were investigated in 77 male and female adult Vietnamese falciparum malaria patients randomly assigned to treatment with either 500 mg of artemisinin daily for 5 days (group A; n = 40) or artemisinin at a dose of 100 mg per day for 2 days, with the dose increased to 250 mg per day for 2 consecutive days and with a final dose of 500 mg on the fifth day (group B; n = 37). Parasitemia was monitored every 4 h. The average parasite clearance time was longer in group B than in group A (means ± standard deviations, 50 ± 23 and 34 ± 14 h, respectively; P < 0.01). Artemisinin concentrations in saliva samples obtained on days 1 and 5 were quantified by high-performance liquid chromatography. The average oral clearance, based on saliva drug concentrations in group B patients, was twofold higher than that in group A patients on day 1 (P < 0.01), with no differences in drug half-lives (P = 0.40), indicating a saturable first-pass metabolism. Female patients had higher oral clearance values on day 1. Artemisinin's pharmacokinetic parameters were similar on day 5 in both groups, although a significant increase in oral clearance from day 1 to day 5 was evident. Thus, artemisinin exhibited both dose- and time-dependent pharmacokinetics. The escalating dose studied did not result in higher artemisinin concentrations toward the end of the treatment period.

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