Comparison of pharmacokinetic and pharmacodynamic profiles of aspirin following oral gavage and diet dosing in rats
Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., Rm. 2116, Bethesda, MD 20892, United States. Chemico-biological interactions
(Impact Factor: 2.58).
11/2008; 179(2-3):233-9. DOI: 10.1016/j.cbi.2008.10.008
Aspirin is one of the oldest drugs and has been purported to have multiple beneficial effects, including prevention of cardiovascular disease and cancer, in addition to its original indication for treatment of inflammation, fever and pain. In cancer chemoprevention studies using animal models, two methods of aspirin administration have been employed: oral gavage and diet. The untested assumption was that exposure and the resultant pharmacological effects are similar for these two administration methods when dosing is normalized on the basis of mg/kg body weight/day. This study examined and compared time-dependent plasma and colon mucosal concentrations of aspirin metabolite salicylate (aspirin concentrations were below level of quantification), plasma thromboxane B(2) concentrations, and colon mucosal prostaglandin E(2) concentration following these two different dosing paradigms in rats. Diet dosing yielded relatively constant plasma and colon salicylate concentration vs. time profiles. On the other hand, oral gavage dosing led to a rapid peak followed by a fast decline in salicylate concentration in both plasma and colon. Nevertheless, the exposure as measured by the area under plasma or colon concentration-time curve of salicylate was linearly related to dose irrespective of the dosing method. Linear relationships were also observed between colon and plasma salicylate areas under the curve and between colon prostaglandin E(2) and plasma thromboxane B(2) areas under the curve. Therefore, more easily accessible plasma salicylate and thromboxane B(2) concentrations were representative of the salicylate exposure and prostaglandin E(2) pharmacodynamic biomarker in the target colon, respectively.
Available from: Robert Chapin
- "concentration of salicylic acid after administration of a single gavage dose (embryo concentration was three times higher); assumes that 100% of teratogenic maternal aspirin dose is converted to salicylic acid, supported by pharmacokinetics in male rats at dose levels of aspirin that were teratogenic in pregnant rats Kimmel et al. (1971); Gupta et al. (2003); Kapetanovic et al. (2009) "
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ABSTRACT: Validation of alternative assays requires comparison of the responses to toxicants in the alternative assay with in vivo responses. Chemicals have been classified as "positive" or "negative" in vivo, despite the fact that developmental toxicity is conditional on magnitude of exposure. We developed a list of positive and negative developmental exposures, with exposure defined by toxicokinetic data, specifically maternal plasma Cmax . We selected a series of 20 chemicals that caused developmental toxicity and for which there were appropriate toxicokinetic data. Where possible, we used the same chemical for both positive and negative exposures, the positive being the Cmax at a dose level that produced significant teratogenicity or embryolethality, the negative being the Cmax at a dose level not causing developmental toxicity. It was not possible to find toxicokinetic data at the no-effect level for all positive compounds, and the negative exposure list contains Cmax values for some compounds that do not have developmental toxicity up to the highest dose level tested. This exposure-based reference list represents a fundamentally different approach to the evaluation of alternative tests and is proposed as a step toward application of alternative tests in quantitative risk assessment.
© 2014 Wiley Periodicals, Inc.
Birth Defects Research Part B Developmental and Reproductive Toxicology 12/2014; 101(6). DOI:10.1002/bdrb.21132 · 0.77 Impact Factor
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ABSTRACT: The degradation of aspirin (ASA) was investigated to reveal information about the influence of complexation with fulvic acid (FA), as a new complexing agent and compared with hydroxy propyl-beta-cyclodextrin complex.
ASA was complexed with FA in the molar ratio 1:0.5, 1:1, and 1:2 by different methods through lyophilization, solvent evaporation, and spray drying. Spray-dried (1:1) ASA-hydroxy propyl-beta-cyclodextrin complex was prepared and compared with optimized complex of FA. All the complexes and ASA alone were packaged in well-labeled sealed polythene-lined aluminum pouches and stored in stability chamber at 40 +/- 2 degrees C and 75 +/- 5% relative humidity for 120 days. Samples were analyzed for salicylic acid content at 0, 30, 60, 90, and 120 days.
Overall 4.31% salicylic acid was formed in 1:1 ASA-FA spray-dried complex, which was optimized stable complex among other complexes of FA prepared by different methods in different molar ratios. However, 2.35% salicylic acid was measured with 1:1 spray-dried ASA-hydroxy propyl-beta-cyclodextrin complex. Stability of ASA increased more when complexed with hydroxy propyl-beta-cyclodextrin as compared to FA.
A novel complexing agent in the form of FA was investigated to increase the stability of ASA. A marked improvement in stability of ASA was observed when complexed with hydroxy propyl-beta-cyclodextrin (1:1) by spray drying as compared to 1:1 spray-dried ASA-FA complex.
Drug Development and Industrial Pharmacy 10/2009; 36(4):428-30. DOI:10.3109/03639040903225091 · 2.10 Impact Factor
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ABSTRACT: Salicylic acid (SA), the active ingredient of aspirin, is effective in various medical treatments such as cosmetology and anticancer therapy. We investigated the photophysical and photochemical behavior of SA using 266 nm laser flash photolysis. Results demonstrate that SA can be photoionized and photoexcited by 266 nm photons to give SA+· and 3SA*. SA is highly photosensitive and can be photoionized via a monophotonic process with a quantum yield of 0.21. Under the aerobic conditions we find that in cells, hydrated electrons easily combine with oxygen to generate O-·20 , which can kill cancer cells. SA+·can be converted into neutral radicals by deprotonation and its pKa value is 2.95. SA also can be oxidized by SO-·4 and the rate constant is 2.28×109 L·mol-1·s-1, which further confirms the photoionization ability of SA. In addition, SA can be excited to 3SA*, which then generates 1O2*. This research provides introductory theory for the potential of SA to be used as an anticancer drug.
ACTA PHYSICO-CHIMICA SINICA 01/2010; 26(1). · 0.85 Impact Factor
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