Metabolism mechanisms pharmacokinetics

Some important conclusions emerge even from this rudimentary profile of mechanisms. Pharmacokinetics and metabolism are as significant in carcinogenesis as they are in the production of other forms of... 

Calleman, C.J. 1996. The metabolism and pharmacokinetics of acrylamide Implications for mechanisms of toxicity and human risk estimation. Drug Metab. Rev. 28(4) ... 

Modifying factors can be used to adjust the uncertainty factors if data on mechanisms, pharmacokinetics, and the relevance of the animal response to human risk justify such modifications. For example, if there is kinetic information suggesting that rat and human metabolisms are very similar for a particular compound, producing the same active target metabolite, then, rather than using a 10-fold uncertainty factor to divide the NOAEL from the animal toxicity study to obtain a human relevant RfD, a factor of 3 for that uncertainty factor might be used. Of particular interest is the new extra 10-fold Food Quality and Protection Act (FQPA) factor, added to ensure protection of infants and children. 

Although these sex-related differences in metabolism have been known for a long time, there is very little data available concerning the role of gender in the metabolism and pharmacokinetics of drugs of abuse. For some drugs of abuse, sexual dimorphism could have important implications and adverse consequences. For PCP, a subject of this discussion, metabolism is the major mechanism for inactivation of pharmacological effects (Mayersohn 1985). In... 

There are other types of studies that can be used to support the likelihood of occurrence of adverse health effects on people. There are metabolic and pharmacokinetic studies, which can describe the mechanism of action of a compound. If we look at the metabolism of an animal versus a human, evidence for toxic effects in humans may be deduced. Considerable species variation exists with respect to benzene metabolism. Metabolism studies of benzene showed that mice metabolize benzene faster than rats and convert more of the benzene to toxic metabolites than do rats, primarily at exposure levels up to about 200 ppm. This is partly due to increased inhalation per unit body weight but also due to a higher activity of hepatic metabolism. From in vitro experiments with hepatocytes or liver microsomes it was shown that the range of metabolite production from human tissue more or less spans the range between mice and rats. 

Table III describes the characteristics of the test substance to be considered. Although in the case of carcinogenesis, we do not know the mechanisms involved, there are inherent biological and chemical properties which can indicate limits to the potential reactivity of chemicals with mammalian cell constituents. These include chemical similarity to other known toxins, binding or adduct formation with cell macromolecules, genotoxicity or activity in short-term tests for carcinogenicity, metabolic and pharmacokinetic data, and other pertinent physiological, pharmacological or biochemical properties.

Thoroughly planned preparation and chemical purity of the radiolabeled drug are of essential importance for the success of pharmacokinetic and metabolic studies. It is desirable that the label site in the drug molecule is not lost through any probable metabolic mechanism. In cases, in which the drug is divided into two major entities, it may become necessary to label both portions. 

Analysis of human CE by Northern blot shows a single band of approximately 2.1 kilobases (kb) (Riddles et al. 1991), and three bands of approximately 2-, 3-, and 4.2-kb occurring with hCE-2 (Schwer et al. 1997). The intensities of the 2.1-kb band were liver 3> heart > stomach > testis > kidney = spleen > colon > other tissues. For hCE-2, the 2-kb band was located in liver > colon > small intestine > heart, the 3-kb band in liver > small intestine > colon > heart, and the 4.2-kb band in brain, testis, and kidney only. Analysis of substrate structure versus efficiency for ester (pyrethroid substrates) revealed that the two CEs recognize different structural features of the substrate (i.e., acid, alcohol, etc.). The catalytic mechanism involves the formation of an acyl-enzyme on an active serine. While earlier studies of pyrethroid metabolism were primarily performed in rodents, knowledge of the substrate structure-activity relationships and the tissue distribution of hCEs are critical for predicting the metabolism and pharmacokinetics of pesticides in humans. Wheelock et al. (2003) used a chiral mixture of the fluorescent substrate cyclopro-panecarboxylic acid, 3-(2,2-dichloroethenyl)-2,2-dimethyl-, cyano(6-methoxy-2-naphthalenyl)methyl ester (CAS No. 395645-12-2) to study the hydrolytic activity of human liver microsomes. Microsomal activity against this substrate was considered to be low (average value of ten samples 2.04 0.68 nmol min mg ), when compared to p-nitrophenyl acetate (CAS No. 830-03-5) at 3,700 2,100 mg ... 

While the exact mechanism of action of procarbazine is unknown, it does inhibit DNA, RNA, and protein synthesis. The pharmacokinetics have never been fully characterized, but it is known that the drug is metabolized extensively. Procarbazine is used most often in the treatment of lymphoma. 

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