Drug metabolism pathways

Steinstrasser, I., and Merkle, H. P Dermal metabolism of topically applied drugs Pathways and models reconsidered. Pharm. Acta Helv. 70(l) 3-24, 1995. 

Since both l]/2 and /cei are constant for elimination processes following first order kinetics, Cl will also be constant. Flowever, should the order of the elimination change due to a change in the biological situation, such as the drug concentration increasing to the point where it saturates the metabolic elimination pathways, then clearance may not be constant. 

Combined Variants in Drug Metabolism and Receptor Genes Value of Drug Pathway Analysis... 

The liver metabolizes drugs, other foreign chemical compounds (xenobiotics), and certain endogenous substances (e.g., steroid hormones, bilirubin) by a variety of pathways. They include hepatic microsomal-mediated oxidative reactions, reductive and hydrolytic reactions (phase I), and conjugation (synthetic) reactions with various endogenous substances (phase II) [58,59] j metabolic reactions occur ubiqui-... 

Metabolic drug-drug interaction results from the alteration of the metabolic clearance of one drug by a coadministered drug. There are two major pathways of metabolic drug-drug interactions. 

The ability of the drug in question to inhibit the activities of known pathways for drug metabolism is evaluated. If a drug is an inhibitor of a drug-metabolizing enzyme pathway, it will have the potential to cause inhibitory drug interactions with coadministered drugs that are substrates of the inhibited pathway. 

Table 5-7. Experimental conditions to reduce the activity of the major drug-metabolizing enzyme pathways using the in vitro experimental systems for drug metabolism...

Harrigan, G. 2002. Metabolic profiling Pathways in drug discovery. Drug Discov. Today 7, 351-352. 

Generally, the formation of toxic metabolites is not the only pathway of biotransformation, and the overall metabolism is constituted toward detoxication and bioactivation processes. The toxic metabolites are themselves often further detoxified. The duality between a beneficial detoxication phenomenon (metabolism, drug resistance) and the occurrence of a toxic effect represents the cost for adaptability of metabolic enzymes to the diversity of xenobiot-ics. For those interested, a recent review applies the above chemistry to predict drug safety. 

Antidepressants are commonly used in combination with antipsychotics to treat depressive symptoms in individuals with schizophrenia. Different antidepressants have been reported to inhibit metabolism of different P450 pathways. Table 66-10 summarizes the potential metabolic drug interactions between antidepressants and SGAs. Potential enzyme inhibitor interactions with clozapine are the most clinically significant. Increased clozapine serum concentrations with a CYP 1A2 inhibitor such as fluvoxamine may precipitate seizures. With the newer atypical antipsychotics, enzyme inhibitors are more likely to cause side effects such as increased sedation, orthostatic hypotension, or increased risk of akathisia and other extrapyramidal side effects. 

Inhibitor (Inhibits Substrate) 1A2 Substrate (Drug Metabolized By Pathway) 2D6 iA3/4... 

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