Overview Of Bioactivation

Drug attrition during the development stage is high and puts a strain on the pharmaceutical industry. Preclinical and clinical toxicity is responsible for about one-third of the attrition of compounds in development, and this number has been gradually increasing (Kola and Landis 2004). Initiatives have been taken by industry-wide organizations such as PhRMA to address this issue, and new studies, for example the recently published research on finding more-predictive markers for kidney toxicity (Ozer et al. 2010), may assist this situation.

Reactive metabolites have been implicated in some cases of toxicity, but the link between reactive metabolites and toxicity is complex and in most cases difficult to establish. The liver is frequently the target organ of reactive metabolites because of the high levels of drug and drug metabolizing enzymes in the liver. A well-established example is the severe hepatoxicity associated with bioactivation of acetaminophen to N-acetyl-p-quinoneimine (NAPQI) at high doses. After saturating the detoxification conju-gative pathways and depleting intracellular glutathione (GSH), NAPQI reacts with critical cellular protein nucleophiles and produces cellular necrosis (see Fig. 6.2).

Interaction with macromolecules

Acetaminophen

NAPQI

Detoxification

Acetaminophen

Interaction with macromolecules

NAPQI

Detoxification

Hepatotoxicity

O-SO3

O—Glucuronide

Figure 6.2. Cytochrome P450-mediated bioactivation of acetaminophen.

O-SO3

O—Glucuronide

Figure 6.2. Cytochrome P450-mediated bioactivation of acetaminophen.

In other cases, any observed toxicity may be rare and idiosyncratic and can lead to disorders such as a severe rash. The problem with idiosyncratic toxicity is that, by definition, it is rare and unpredictable and, therefore, may escape observation in clinical trials. In addition, idiosyncratic toxicity does not appear to be dose dependent. Finally, some reactive metabolites react with genetic material.

For all the above reasons, most pharmaceutical companies have established assays to determine the bioactivation of drug candidates. Reactive metabolites are usually short lived and, therefore, difficult to detect directly. Thus, assays that monitor surrogate endpoints have been employed:

• Trapping reactive metabolites with GSH, cyanide, methoxyla-mine, semicarbazide, or other nucleophiles.

• Measuring the extent of covalent modification of proteins.

• Determining the time-dependent inhibition of cytochrome P450 (P450) enzymes.

• Monitoring the formation of stable metabolites that points to formation of reactive metabolites, such as the detection of car-boxylic acids from terminal acetylenes.

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Detoxification and Weight Loss

Detoxification and Weight Loss

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