Liver biotransformation

Genetic differences. Patients show a wide variation in both the extent of liver biotransformation and the range of metabolic pathways used to eliminate drugs. Differences in the metabolism of the drug can lead to a smaller clinical effect than desired, a greater clinical effect than desired (e.g., an antihypertensive causing hypotension), or a more toxic effect than desired. 

Many factors have a profound influence on the pharmacokinetics of drugs and consequently on a patient s pharmacological response (Box 33-1). For example, the consideration of the patient s history, with particular emphasis on theirpathophysiological state and adjunct drug therapy, is essential at the initiation of drug therapy and TDM. Other important factors include how a drug is absorbed, distributed, metabolized, cleared by the Liver, biotransformed, and excreted. 

Hyotylainen T, Oikari A. 1999a. Assessment of the bioactivity of creosote-contaminated sediment by liver biotransformation system of rainbow trout. Ecotoxicol Environ Saf 44 253-258. 

After oral dosing, plasma concentrations of statins peak in 1 hours. The half-lives of the parent compounds are 1 hours, except for atorvastatin and rosuvastatin, which have half-lives of-20 hours, which may contribute to their greater cholesterol-lowering efficacy. The liver biotransforms all... 

Plant biotransformation parallels liver biotransformation and is conceptually divided into three phases. Phase I typically consist of oxidative transformations in which polar functional groups such as OH, NH2, or SH are introduced. However, reductive reactions have been observed for certain nitroaromatic compounds. Phase II involves conjugation reactions that result in the formation of water soluble compounds such as glucosides, glutathiones, amino acids, and malonyl conjugates or water-insoluble compounds that are later incorporated or bound into cell wall biopolymers. In animals, these water-soluble Phase H metabolites would typically be excreted. In Phase III, these substances are compartmentalized in the plant vacuoles or cell walls. For additional details, the reader is referred to reviews on the subject by Komossa and Sandermann (1995), Pflugmacher and Sandermann (1998), and Burken (2003). Enzymatic conversion rates typically follow Michaelis-Menten kinetics and are temperature-dependent (Larsen et al., 2005 Yu et al., 2004,2005, 2007). 

Materials may be absorbed by a variety of mechanisms. Depending on the nature of the material and the site of absorption, there may be passive diffusion, filtration processes, faciHtated diffusion, active transport and the formation of microvesicles for the cell membrane (pinocytosis) (61). EoUowing absorption, materials are transported in the circulation either free or bound to constituents such as plasma proteins or blood cells. The degree of binding of the absorbed material may influence the availabiHty of the material to tissue, or limit its elimination from the body (excretion). After passing from plasma to tissues, materials may have a variety of effects and fates, including no effect on the tissue, production of injury, biochemical conversion (metaboli2ed or biotransformed), or excretion (eg, from liver and kidney). 

The kinetic properties of chemical compounds include their absorption and distribution in the body, theit biotransformation to more soluble forms through metabolic processes in the liver and other metabolic organs, and the excretion of the metabolites in the urine, the bile, the exhaled air, and in the saliva. An important issue in toxicokinetics deals with the formation of reactive toxic intermediates during phase I metabolic reactions (see. Section 5.3.3). 

Huang YS, Sultatos LG. 1993. Glutathione-dependent biotransformation of methyl parathion by mouse liver in vitro. Toxicol Lett 68 275-284. 

Radulovic LL, Kulkami AP, Dauterman WC. 1987. Biotransformation of methyl parathion by human foetal liver glutathione S-transferases An in vitro study. Xenobiotic 17 105-114. 

Zhang HX, Sultatos EG. 1991. Biotransformation of the organophosphorus insecticides parathion and methyl parathion in male and female rat livers perfused in situ. Drug Metab Dispos 19 473-477. 

In a study of metabolism of 14C-flocoumafen by the Japanese quail (Huckle et al. 1989), biotransformation was extensive and rapid, with eight metabolites detected in excreta. The elimination of radioactivity from the liver of Japanese quail was biphasic (Figure 11.2). After an initial period of rapid elimination, there followed a... 

Metabolism The sum of anabolism and catabolism, although also used to describe the biotransformation of drugs in the liver. 

Metabolic stability in human liver preparations may represent a suitable experimental tool to obtain relevant pharmacokinetic information in an early phase of drug discovery. Compounds which are metabolized principally by the liver can be identified and studied in more detail to determine the principal sites of biotransformation. 

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