Human Drug Metabolism

Aromatic ring hydroxylation (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

Nature of aromatics Large, highly lipophilic, planar and stable molecules with few, if any, vulnerable functional groups look to be a difficult proposition to metabolize (Figure 3.8). Indeed, if there are any aliphatic groups, or non-aromatic rings associated with an aromatic molecule, these will often be attacked rather than the aromatic group. The ring hydroxylation […]

Alkyl oxidations (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

The saturated bonds of straight chain aliphatic molecules are very stable; indeed, they can be even harder to break into from the thermodynamic point of view than aromatic rings, whilst molecules with unsaturated bonds are the easiest to oxidize. Straight chain aliphatic molecules are easier to oxidize if they have an aromatic side chain. Alkyl […]

‘Rearrangement’ reactions (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

The use of oxidation as a tool to rearrange molecules to less lipophilic products has the added benefits of unmasking other vulnerable groups and making the products simpler to conjugate. There are several CYP-mediated oxidations that have this effect on molecules. Dealkylations Alkyl groups, especially bulky ones, are very lipophilic and often are attached to […]

Other oxidation processes (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

Primary amine oxidations Primary amines found in sulphonamides and sulphones can be metabolized to hydroxylamines and their toxicity hinges on these pathways.The hydroxylamines formed are often reactive and although they can be stabilized by glutathione (GSH) and other cellular antioxidants, they can spontaneously oxidize in the presence of oxygen to nitroso and then nitro-derivatives. The […]

Control of CYP metabolic function (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

Although CYPs appear to be part of an impressive and flexible system for the oxidation of drugs, it is not enough just to process endogenous and xenobiotic molecules at a set rate. Endogenous and exogenous CYP substrates can vary enormously in their concentrations within the body, even on a day-to-day basis. As we have seen, […]

Causes of accelerated clearance (Induction of Cytochrome P450 Systems) (Human Drug Metabolism)

Introduction The aim of drug therapy is to provide a stable, predictable pharmacological effect that can be adjusted to the needs of the individual patient for as long is deemed clinically necessary. The physician may start drug therapy at a dosage that is decided on the basis of previous clinical experience and standard recommendations. At […]

Enzyme induction (Induction of Cytochrome P450 Systems) (Human Drug Metabolism)

Types of inducer There are several broad groups of drugs and chemicals capable of inducing hepatic metabolism: these include: •    Anticonvulsants, mainly the older established drugs, such as phenytoin, car-bamazepine and phenobarbitone. Topiramate and oxcarbazepine are weaker inducers. These drugs induce many CYP isoforms, including CYPA2, CYP2C8/9, CYP2C19 and CYP3A4/5. • Steroids, such as dexamethasone, […]

Mechanisms of enzyme induction (Induction of Cytochrome P450 Systems) (Human Drug Metabolism) Part 1

Introduction The process by which enzyme induction occurs has three main requirements: •    The hepatocyte must detect the presence of particular potentially persistent lipophilic drugs and/or toxins and correctly sense their concentration. •    The process of detection is translated into an increase in the capability of the appropriate metabolic system or systems within the cell, […]

Mechanisms of enzyme induction (Induction of Cytochrome P450 Systems) (Human Drug Metabolism) Part 2

PXR mediated control of CYP expression The main NR usually associated with the control of the CYP3A series is PXR, although as mentioned above CAR is also heavily involved. PXR is also known as the SXR (steroid and xenobiotic receptor) and is classified in the nuclear receptor family as NR1I2. Although PXR is a nuclear […]

Induction – general clinical aspects (Induction of Cytochrome P450 Systems) (Human Drug Metabolism)

From a clinical standpoint, important features of enzyme induction can be summarized: •    The process is relatively slow, i.e. usually days or even weeks. •    The potential changes in drug concentrations can be great enough to cause treatment failure. •    The induction process is usually, but not always, reversible over a similar time frame to […]

← Previous Entries

Next Entries →