Dosing vehicles

Oral absorption of trichloroethylene in animals is rapid but can be influenced by fasting and the dosing vehicle. Trichloroethylene doses of 5, 10, and 25 mg/kg in 50% aqueous polyethylene glycol 400 were administered to nonfasted rats, and a 10-mg/kg dose was administered to rats that were fasted for 8-10 hours (D Souza et al. 1985). Trichloroethylene was rapidly and completely absorbed in the fasted rats, with peak... 

Collins BJ, Goehl TJ, Jameson CW, et al. 1986. Analytical methods for determination of neat and microencapsulated trichloroethylene in dosing vehicles and whole blood. J Anal Toxicol 10 236-240. 

Medicinal chemists should be aware that inexperienced biologists can erroneously conclude that poorly aqueous soluble compounds are orally absorbed when compounds are dosed in pharmaceutically unacceptable solvents. Always ask what is the dosing vehicle Heroic combinations of DMSO, Cremophor, poly(ethylene glycol), Tween-80 and ethanol are unacceptable and misleading. In case of doubt consult with a pharmaceutical scientist colleague. The reliable standards are an aqueous solution (with perhaps a trace of DMSO) or a suspension (perhaps stabilized with an acceptable quantity of adjuvant, e.g. Tween-80). 

When compounds are selected for preliminary PK studies, the identification of an appropriate dosing vehicle for iv studies requires solubility studies in various vehicles. Also, the study of thermodynamic solubility is useful as this more closely reflects the environment experienced by compounds on oral dosing. Higher throughput thermodynamic solubility assays have been introduced recently [23] so it will be possible to introduce this type of assay earlier in the discovery process. 

Shou, W. Z. Naidong, W. Postcolumn infusion study of the dosing vehicle effect in the liquid chromatography/tandem mass spectrometric analysis of discovery pharmacokinetic samples. Rapid Commun Mass Spectrom 2003, 17, 589-597. 

Kim FIJ, Bruckner JV, Dallas CE, et al. 1990a. Effect of dosing vehicles on the pharmacokinetics of orally administered carbon tetrachloride in rats. Toxicol AppI Pharmacol 102 50-60. 

Pharmacokinetics Absorption is variable and dependent upon many factors including integrity of skin, dose, vehicle used, and use of occlusive dressings. Small amounts maybe absorbed from the skin. Metabolized in liver. Excreted in the urine and feces. 

Raymond, P. Plaa, GL. (1997) Effect of dosing vehicle on the hepatotoxicity of CCI4 and nephrotoxicity of CHCI3 in rats. J. Toxicol, environ. Health, 51, 463-476... 

They are not a suitable dosing vehicle for certain drugs. 

Occasionally, interfering peaks are observed from metabolites, dosing vehicles, or the sample matrix itself. Suppression and interfering peaks can often be eliminated by changing the MS conditions, including the source type and resolving power... 

The SRM/EMS mode of operation provided information on the coeluting glucur-onide conjugates and the PEG dosing vehicle. Information about the coeluting... 

Black, K., Erol, H., and Di Bussolo, J. M. (2006). Dealing with detergents and dosing vehicles in samples submitted for LC-MS analysis. In Proceedings of the 54th ASMS Conference on Mass Spectrometry and Allied Topics, Seattle, WA. 

When constructing the GLMM to perform the model-based /-test, the terms within the model include the dye (to model dye-effects), the microarray (to model any random microarray-specific effects), and the dose (including vehicle, to model dose/vehicle effects). 

This chapter provides an overview of factors affecting dermal absorption. Factors influencing absorption are among others related to the skin (e.g. anatomical site, difference between species, metabolism, etc.) and the exposure conditions (e.g. area dose, vehicle, occlusion and exposure duration). In order to provide relevant information for the risk assessment of pesticides, dermal absorption studies should take these aspects into account. With respect to the methods being used nowadays for the assessment of dermal absorption, it is important to realize that neither in vitro nor in vivo animal studies have been formally validated. Available data from various in vitro studies, however, indicate that the use of the total absorbed dose (i.e. the amount of test substance in the receptor medium plus amount in the skin) could be used in a quantitative manner in risk assessment. Tape stripping of the skin can be adequate to give a good indication of test chemical distribution, and hence its immediate bioavailability. 

The effect of dosing vehicle excipients such as PEG400, propylene glycol. Tween 80, and hydroxypropyl-P-cyclodextrin on the accuracy of pharmacokinetic analysis by LC-MS was investigated as well [89-90]. Due to matrix effects, the analysis may indicate a 2-5-fold increase in the calculated plasma clearance. This would result in a false rejection of the compound in a drag discovery screen. Similar effects of dosing vehicle excipients were also investigated via post-column infusion studies by others [79, 85, 91]. 

Dose, vehicle concentration, vehicle volume Area of skin dosed... 

Eor parenteral nutrition drug-free emulsions are used. A typical composition of a nutritional fat emulsion for i.v. administration is 200 g soybean oil or safflower oil, 12 g egg phospholipids and 25 g glycerine per liter of emulsion with the pH adjusted to within the range 5.5-8. It is most important that the fat droplet particle size that does not exceed 0.5 pm. For experimental purposes, such fat emulsions (e.g. Abbolipid , IntraUpid , Lipofundin ) are well suited and used as early dosing vehicles for lipophilic drug candidates. 

Shou, W.Z. Naidong, W. Post-Column Infusion Study of the Dosing Vehicle Effect in the Liquid Chromatography/Tandem Mass Spectrometric Analysis of Discovery Pharmacokinetic Samples, Rapid Commun. Mass Spectrom. 17, 589-597 (2003). 

Compound Log P Lipid Solubility Dosing vehicle Cumulative lymphatic transport (% dose) Collection period Model Ref. 

King et al. [164] used Q-Trap to simultaneously quantify an NCE and collect information about circulating metabolites, dosing vehicle, interfering matrix components, and co-eluting metabolites. The ability to operate the LIT in the enhanced MS (EMS) mode with a scan speed of 4000 Th/s allowed the combined SRM transitions (parent/IS) and the full scans to be completed in 0.31 s. The quantification data... 

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