Toxicity, mechanisms pharmacokinetics

All therapeutically active agents in the nitrate group have identical mechanisms of action and similar toxicities. Therefore, pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates. 

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. 

Stereochemistry of the local anesthetics, however, plays an important role in their observed toxicity and pharmacokinetic properties. For example, ropivacaine and levobupivacaine, the only optically active local anesthetics currently being marketed, have considerably lower cardiac toxicities than their close structural analogue, bupivacaine (45). Furthermore, the degree of separation between motor and sensory blockade is more apparent with ropivacaine and levobupivacaine relative to bupivacaine at a lower end of the dosage scale (46). Thus, the observed cardiac toxicity of bupivacaine has been attributed to the F -( + )-bupivacaine enantiomer (41,42,43). The exact mechanisms for this enantiomeric... 

The requirements of protease inhibitors as drugs in terms of potency, pharmacokinetics, and toxicity will vary depending on the nature of the infection and the goals of therapy. At one extreme is treatment of HlV-1, a chroific infection that requires life-long therapy and full suppression of viral replication. At the other extreme is the treatment of human rhinovirus (i.e., the cold virus), where short-term treatment to blunt viremia will likely be sufficient to reduce the unwanted symptoms of a cold. In all cases, viral proteases represent very attractive targets with familiar mechanisms of catalysis that frequently allow for the design of transition state analogs and with distinct specificities from host proteases. 

A knowledge of physiology and pharmacokinetics is needed (Fanis et al. 1993 Monteiro and Furness 2001). Levels of mercuiy normally vary among internal tissues, and the time to equilibrate within each tissue varies. For example, blood mercury levels normally reflect veiy recent exposure, while brain and liver levels reflect longer-term exposure. Tissue-specific mechanisms of detoxification and seqnestration, among other processes, must be understood to define the bioactive moiety in observed tissue bmdens before a clear expression of toxicity can be derived (Woodetal. 1997). 

While carboplatin has the same mechanism of action as cisplatin, it has a much less toxic side-effect profile than cisplatin. The pharmacokinetics of carboplatin are best described by a two-compartment model, with an a half-life of 90 minutes and a terminal half-life of 180 minutes. Carboplatin is eliminated almost entirely by the kidney by glomerular filtration and tubular secretion. Many chemotherapy regimens dose carboplatin based on an area under the curve (AUC), which is referred to... 

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