Human Drug Metabolism

Inhibition of metabolism – general aspects (Cytochrome P450 Inhibition) (Human Drug Metabolism)

Introduction The previous topic was mostly aimed at problems associated with drug failure due to enzyme induction. However, when drug clearance is slowed or even stopped for any reason, the consequences are more dangerous and occur much more rapidly compared with enzyme induction. Generally, the intended pharmacological effects of the drugs will be greatly intensified, […]

Mechanisms of inhibition (Cytochrome P450 Inhibition) (Human Drug Metabolism) Part 1

General aspects of inhibition Enzymes and tissue/cell receptors share similar features. A receptor binds a molecule that then acts like a switch to trigger a cascade of molecules to instruct the cell to perform a function. The molecule must fit the receptor precisely and then trigger the cascade, like a key, which first enters a […]

Mechanisms of inhibition (Cytochrome P450 Inhibition) (Human Drug Metabolism) Part 2

Mechanism-based inhibitors: grapefruit juice Although patients have been heroically consuming grapefruit juice for their health for decades, it took until the late 1980s before its effects on drug clearance were noted and several more years before it was realized that there could be a major problem with drug interactions (History 1). This led to the […]

Cell transport systems and inhibition (Cytochrome P450 Inhibition) (Human Drug Metabolism)

Uptake (Influx) transporters: OATPs The main hepatic and gut uptake solute carriers (SLCs), or transporters, are known as organic anion transporting peptides, or OATPs.Swapping cellular molecules such as glutathione for extracellular endogenous anions and some predominantly polar drugs. In the context of this topic, ‘inhibition’ particularly of CYPs has so far translated into accumulation and […]

Major clinical consequences of inhibition of drug clearance (Cytochrome P450 Inhibition) (Human Drug Metabolism)

Introduction Although CYP inhibition can be competitive, non-competitive, uncompetitive or mechanism dependent, in clinical practice the main concern is how rapidly the inhibitor causes drug levels to climb towards toxicity and whether the toxic effects can be treated before serious injury or death results. As has been mentioned already, there are a number of major […]

Use of inhibitors for positive clinical intervention (Cytochrome P450 Inhibition) (Human Drug Metabolism)

Introduction The effects of inhibitors on the concentrations of CYP substrates can be so dramatic that it has occurred to a number of scientists and clinicians to explore various strategies to exploit this effect to provide some form of benefit to the patient. This can take the form of preventing the formation of a toxic […]

Conjugation and Transport Processes (Conjugation and Transport Processes) (Human Drug Metabolism) Part 1

Introduction This lipophilicity and stability also means that they are very hard to control. In this context, control entails the termination of biological function and subsequent removal from the body. With steroid hormones, for example, the ability to modulate synthesis and destruction allows the exertion of exceedingly fine control over the structural and biochemical changes […]

Conjugation and Transport Processes (Conjugation and Transport Processes) (Human Drug Metabolism) Part 2

UGTs and bilirubin As with all biotransforming enzymes, the endogenous functions of UGTs are part of cellular ‘housekeeping’. Of the 16 human UGTs the most important is UGT1A1, which plays a key homeostatic role in bilirubin processing. Once erythrocytes have reached the end of their lifespan, they are dismantled and the major waste product is […]

Sulphonation (Conjugation and Transport Processes) (Human Drug Metabolism)

Introduction Sulphonation is accomplished by a set of enzyme systems known as sulphotransferases (SULTs) and they are found in most tissues to varying degrees of activity. The major sites of activity are the liver, small intestine, main intestine and colon, although they are also found in the brain and the placenta. The main detoxifying isoforms […]

The GSH system (Conjugation and Transport Processes) (Human Drug Metabolism)

Introduction One of the main problems with the oxidation of various molecules by CYP enzymes is that they are often destabilized and sometimes form highly reactive products. The analogy used previously in this topic was that of a child given a hammer and told to hit anything metallic hard. CYPs occasionally form metabolites so reactive […]

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