Drug and toxicity

Drugs and toxicants are metabolized in the human body in such a way that more polar compounds are usually formed. Therefore to decrease the polarity and increase the volatility and thermal stability of the analytes, the derivatization step is an unavoidable requirement for GC analysis. This step enhances the detectability of the analytes and provides very characteristic mass spectra that can be relevant for identification purposes. Most analytes do not require derivatization for LC separation and MS detection. 

Dosage adjustments must be made to prevent accumulation of drug and toxicity in patients with renal insufficiency. Either the dose of drug is kept constant and the interval between doses is increased, or the interval is kept constant and the dose is reduced. Nomograms and formulas have been constructed relating serum creatinine levels to adjustments in... 

Figure 5.3d The metabolism of the drug terfenadine. The double lines indicate the inhibition of metabolism by other drugs such as ketoconazole or the natural product found in grapefruit juice. This leads to a rise in the blood level of the drug and toxicity.

Foster, T.J. (1983). Plasmid-determined resistance to antimicrobial drugs and toxic metal ions in bacteria. Microbiological Reviews, 47, 361-409-... 

The first and third routes are important in relation to pharmacokinetic mechanisms. The aqueous pores are too small in diameter for diffusion of most drugs and toxicant, although important for movement of water and small polar molecules (e.g., urea). Pinocytosis is important for some macromolecules (e.g., insulin crossing the blood-brain barrier). 

Most drugs and toxicant pass through membranes by simple diffusion down a concentration gradient. The driving force being the concentration gradient across the membrane. 

Drugs and toxicants with multi-exponential behavior depicted in Figure 6.14 require calculation of the various micro constants. An alternative method involves using model-independent pharmacokinetics to arrive at relevant parameters. Very briefly, it involves determination of the area under the curve (AUC) of the concentration-time profiles. The emergence of microcomputers in recent years has greatly facilitated this approach. 

Marquet, P., N. Venisse, E. Lacassie, et al. 2000. In-source CID mass spectral libraries for the general unknown screening of drugs and toxicants. Analusis 28 925-934. 

AH) polyaromatic genotoxins, teratogens and enzymes involved in drug and toxicant... 

Sauvage FL, Saint-Marcoux F, Duretz B, Deporte D, Lachatre G, Marquet P (2006) Screening of drugs and toxic compounds with liquid chromatography-linear ion trap tandem mass spectrometry. Clin Chem 52 1735-1742... 

So far, there has been little use of ab initio methods for the derivation of QSARs to predict the toxic potency and mode of action of chemicals. The present results indicate that with regard to net atomic charges and charge partial surface area descriptors, ab initio methods may indeed provide a different type of information, which should be kept in mind for future investigations, particularly when focusing on the charge-controlled impact on bioreactivity of drugs and toxicants. 

Some drugs and toxic compounds owe their activities to an ability to form covalent products with important target substances (7,8,9). 

Poch G. 1993. Combined effects of drugs and toxic agents. New York Springer-Verlag. 

Radioimmunassay (RIA) is used to detect and quantify minute quantities of an antigen in biological or environmental samples. RIA is commonly used to measure nonprotein antigens such as drugs and toxicants. This immunoassay is highly quantitative. An example of the use of RIA in toxicology would be the analyses of dioxin levels in the blood of employees from a chlorophenol production plant. 

Figure 11.3. Steady-state concentrations of a hypothetical clinical drug and toxicant in a population that includes extensive metabolizers (EMs) and poor metabolizers (PMs).

Disposition in the Body. Mandelic acid is a urinary metabolite of several drugs and toxic chemicals and is also found endogenously in normal urine at concentrations of up to 5 pg/ml. 

Marquet, P., Saint-Marcoux, F., Gamble, T.N., Leblanc, J.C. (2003). Comparison of a preliminary procedure for the general unknown screening of drugs and toxic compounds using a quadrupole-linear ion-trap mass spectrometer with a liquid chromatography-mass spectrometry reference technique. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 789(1) 9-18. 

Wang T, Shankar K, Ronis MJ, Mehendale HM. Mechanisms and outcomes of drug- and toxicant-induced liver toxicity in diabetes. Crit Rev Toxicol. 2007 37(5) 413-459. 

Table 3 Examples of interactions of drugs and toxicants with apoptosis...

Measurements of motor activity have been used to evaluate the potential central nervous system (CNS) effects of a wide variety of drugs and toxicants. One of the advantages of such measures of motor function is that no training is required of the subject. In addition, measures of motor activity can be made repeatedly across time so that the time course, including the onset and reversibility of toxicant effects, can be determined. In these types of repeated measurement experiments, moreover, an animal can serve as its own control, meaning that the experimenter looks for a change in the animal s normal pattern of motor activity after receiving the toxicant compared to the pattern observed before the treatment. 

One final common inclusion in many studies of occupational behavioral toxicology and in some test batteries is assessments of symptoms experienced by those exposed to chemicals. While this might be perceived as an ostensibly simple procedure, it entails numerous potential confounds. These evaluations are typically administered via questionnaires. Items for the questionnaire must be carefully constructed with respect to not only the choices of items but also the wording of the text and the manner in which the response is recorded. Clearly, the motivation of the subject in answering the questions must be considered. One problem can arise when the list of symptoms includes only those that are associated with the toxicant of concern. It is necessary to include symptoms that are not associated with the particular toxicant under evaluation so that some assessment of the tendency of the subject to respond positively to all symptoms can be evaluated. Several such evaluations of subjective and mood states are available. The most widely used is the Profile of Mood States (POMS), which consists of 65 adjectives of various moods that the subject answers according to a 5-point rating scale. The POMS has been used extensively in the evaluation of the acute effects of CNS drugs and toxicants. 

PHARMACOLOGY AND ANALYSIS OF SPECIFIC DRUGS AND TOXIC AGENTS... 

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