Metabolic inhibitor selectivity

The importance of these enzymes for drug interactions is that enzyme inducers and inhibitors may preferentially affect certain isoforms and consequently may only affect the metabolism of selected drugs. For example, ketoconazole has the potential to inhibit the metabolism of drugs metabolised to a great extent by the sub-family 3A (e.g. midazolam) but not of those metabolised by sub-family 1A (e.g. theophylline), 2C (e.g. diazepam), or 2D (e.g. metaprolol). In contrast, although fluconazole is a weaker inhibitor of the sub-family 3A than ketoconazole, it also inhibits the sub-family 2C, and so the interactions of fluconazole differ from those of ketoconazole. 

In contrast, decreases in theophylline metabolism by selective inhibitors of CYP1A2, such as fluvoxamine and some quinolone antibiotics, or by selective and potent inhibitors of CYP3A4, such as the macrolide antibiotics, have resulted in serious theophylline toxicity (22). It is postulated that taken over time, the macrolide antibiotics act as mechanism-based inhibitors of CYP isoforms other than just CYP3A4. Some nonselective inhibitors of P450s, such as cimetidine, some p-blockers and calcium channel blockers, and others (19,22), also appear to inhibit the metabolism of theophylline enough to cause toxicity. 

Active transport is found in biological desalination and ion separation. Salt excretion by the glands of desert plants and accumulation of potassium in certain bacteria against a very large concentration gradient are some examples of active transport. Active transport is a highly selective process it can be prevented by specific metabolic inhibitors, and is closely related to facilitated transport. 

As described previously, the presystemic metabolism of drugs may occur via various mechanisms. It is obvious, therefore, that coadministration of a low bioavailable drug and its metabolism inhibitor, which can selectively inhibit any of the contributing processes, would result in increased fractional absorption and hence a higher bioavailability. In fact, this approach seems to be a promising alternative to overcome the enzymatic barriers to oral delivery of metabolically labile drugs such as peptides and proteins. 

Why then, since such an abundance of metabolic inhibitors is available, do so few of them find practical application Examples are the folic acid reductase inhibitors, such as aminopterin, the purine and pyrimidine analogs used as cytostatics in cancer chemotherapy and known for their high toxicity in a wide variety of species, and the organic phosphates and carbamates used as insecticides but also highly toxic to mammals. Lack of selectivity in the action of metabolic inhibitors is inherent in their mechanism of action due to the universality of biochemical processes and principles throughout nature. Selectivity in action requires species differences in biochemistry. For the antivitamins, for instance, there is not only a lack of species differences in action in addition, the fact that vitamins often serve as cofactors for a variety of enzymes is a serious drawback to endeavors to obtain agents with species-selective action. 

Metabolic inhibitors may fail even where no species selectivity is required. The antimetabolite A4)5-cholestenone, designed to inhibit cholesterol synthesis, illustrates this it blocks the conversion of desmosterol to cholesterol, the final step in this pathway (Fig. 4). The blockade of cholesterol formation, however,... 

MAO-B inhibitor selective inhibitor of the enzyme that metabolizes dopamine (no t3Tamine interactions). Used in Parkinson s disease. 

Extracellular anandamide, after it serves its function, is rapidly taken up by neuronal and non-neuronal cells by a high-affinity carrier-mediated transport mechanism. This mechanism meets key criteria of carrier-mediated transport, such as fast rate (t, of approximately 4 min), temperature dependence, satura-bility, and substrate selectivity (Beltramo et ah, 1997 Hillard et al., 1997). Furthermore, the transportation of anandamide is independent of sodium ions and is not affected by metabolic inhibitors. The second endogenous camiabinoid, 2-AG, competes for uptake with anandamide. It has been variously reported to exhibit a 2-fold higher affinity for the anandamide transporter than anandamide (Jarrahian et al, 2000), or equal affinity (Piomelli et al, 1999). The molecular structure of this hypothetical anandamide transporter remains unknown. However, it is selective for fatty acid amides or esters, and it is not a fatty acid transporter (Piomelli et al, 1999 Jarrahian et al, 2000). Very recent results indicate that anandamide uptake is a process driven by metabolism and other downstream events, rather than by a specific membrane-associated anandamide carrier (Glaser et al, 2003). 

Proteins may be classified primarily by their sequence or by their function, which may include acting as enzymes, transporters, channels, and receptors (a comprehensive and detailed review would be well beyond the scope of a single book chapter). An alternative way of classifying proteins is to consider the influence they have on drug Absorption, Metabolism, Distribution, Excretion, and Toxicology (ADME/Tox). A complete picture of any one protein system from expression, regulation, substrate and inhibitor selectivity, or protein-protein interaction is not currently feasible. We are therefore left... 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

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