Drugs intrinsic reactions

As with any adverse drug reaction, drug-induced liver disease can be described as intrinsic or idiosyncratic. Intrinsic reactions occnr when... 

Fig. 7.1 Relationship between Drug-related Problems (DRP), Adverse Drug Reaction (ADR), and Adverse Drug Event (ADE). The definitions of extrinsic and intrinsic DRPs have been adapted from van den Bent (2002)... 

High-clearance drugs are those for which there is no saturation of the reaction that converts the drug, and therefore, the clearance rate approaches the blood-flow rate. For capacity-limited drugs, flow rate is irrelevant, and clearance is a simple product of the unbound fraction and the intrinsic clearance. 

Serum chemistry markers play an important role in hepatotoxicity evaluation in human and animal safety studies. The classic markers of hepatotoxicity are alanine aminotransferase (ALT), aspartate aminotrasnferase (AST) and alkaline phosphatase (ALP) [124—127]. Drug-induced hepatotoxicity can be difficult to assess in some circumstances. Hepatotoxic responses can be intrinsic (predictable, dose-related) or idiosyncratic (unpredictable, non-dose-related). ALT, AST and ALP are generally not useful for predicting idiosyncratic responses. The administration of some drugs, such as isoniazid, can lead to a high incidence of ALT elevation, but are tolerated by most patients without severe hepatotoxicity. Adverse drug reactions can be masked... 

Cytochrome b5 affects the kinetics of drug metabolism by certain CYP enzymes hence, coexpression of this microsomal hemoprotein (together with NADPH-CYP reductase) can affect the catalytic efficiency of certain recombinant CYP enzymes (76,109). For example, the presence of cytochrome b5 tends to increase Fmax for reactions catalyzed by CYP3 A4, whereas it tends to decrease Km for reactions catalyzed by CYP2E1. In both cases, cytochrome b5 increases Vmax/Km, which is a measure of in vitro intrinsic clearance. The fact that some commercially available recombinant CYP enzymes are expressed with cytochrome b5 while others are not complicates the interpretation of results of studies performed with recombinant human CYP enzymes. 

Classification of chemically induced hepatotoxicity is primarily based upon pattern of incidence and histopathological morphology. Intrinsic hepatotoxic drugs demonstrate a broad incidence, dose-response relationship and will usually give similar results in humans and experimental animals. The incidence of liver damage from idiosyncratic hepatotoxicants is limited to susceptible individuals and results from hypersensitivity reactions or unusual metabolic conversions that can occur due to polymorphisms in drug metabolism genes (see Chapters 11 and 13). 

Our approach is similar to the system devised by Hansch. The model assumes that the amount of externally applied drug found at the receptor site is related to the partition coefficient. Once the drug reaches the receptor site, the intrinsic activity of the molecules takes over and triggers a reaction which elicits the biological response. The model is illustrated by Equation 1. 

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