Metabolism tissue depots

Pharmacokinetic properties Fentanyl (Scholz et al., 1996) is a highly lipophilic compound and about 80% binds to plasma proteins. After parenteral administration it has a rapid onset and a short duration of action. The compound is rapidly transported into the CNS and lipid tissues. The short duration of action is due to redistribution rather than metabolic inactivation or excretion. It is released from tissue depots with a half-life of about 4 h and the terminal half-life is up to 7 h. The main metabolites, excreted in urine are 4-N-(N-propionylanilino)-piperidine and the N-hydroxypropionyl derivative. 

Adipose tissue is viewed not simply as a passive lipid storage depot but instead as a highly active metabolic tissue, which secretes numerous products that affect insulin resistance either through a traditional (circulating) hormonal effect, or through local effects on the adipocyte. The term adipokines has been used to describe the numerous adipocyte secretory proteins, which include TNFa, IL-6, leptin, PAI-1, resistin, and adiponectin. 

It is now about 10 years since the intensive investigation of adipose tissue began. Until the 1930 s, this tissue was considered a metabolically inert depot of excess calories stored as triglyceride. During the next 3 decades, a series of key observations gradually kindled Interest in the possibility of a more dynamic role of the adipose organ in the body s metabolism ... 

PPARy White adipose tissue, atherosclerotic lesions Insulin-sensitizing and glucoselowering re-directs TG from non-adipose tissues and visceral adipose depots for storage in subcutaneous adipose tissue slowed progression of atherosclerosis Fatty acids, eico-sanoids Th iazolid i ned iones pioglitazone (Actos ), rosiglita-zone (Avandia ) Type 2 diabetes, (insulin resistance, metabolic syndrome)... 

A xenobiotic is said to be stored when it is not available to sites of metabolism or action and is not available for excretion. In other words, it is held in an inert position from a toxicological point of view, where it is not able to express toxic action or to be acted upon by enzymes. A xenobiotic is stored when it is located in a fat depot (adipose tissue), bound to an inert protein or other cellular macromolecule, or simply held in a membrane that does not have any toxicological function (i.e., it does not contain or represent a site of toxic action, neither does it contain enzymes that can degrade the xenobiotic). 

The resynthesized triglycerides invariably contain saturated and unsaturated fatty acids in an approximate 2 1 ratio. Typically, nearly all of the fatty acid content of adipose tissue can be accounted for by just six different types of molecule with palmitate (06 0) and oleate (08 1) together contributing over 75% of the total. Turnover studies suggest that for most people, much of the fat is metabolically relatively inert acting as depot with a long half-life, and only a smaller component of the stored fat being readily accessible. 

Digestion of proteins occurs by enzymatic hydrolysis in the small intestine (Figure 4.3). The digestion of protein produces single amino acids. These can enter the bloodstream through the small intestine walls. The amino acids circulate in the bloodstream until further metabolized or used for protein synthesis there is not a storage depot for amino acids as there is for lipids, which are stored in fat depots in adipose tissue. However, the body does break down protein tissue (muscle) to provide amino acids in the bloodstream. 

Excess adiposity, particularly the abdominal obesity associated with increased waist circumference, is associated with insulin resistance, hypertension, and proinflammatory states. The prevalence of this complex of comorbidities associated with obesity, now referred to as the metabolic syndrome, is reaching epidemic proportions in the United States (Grundy et al., 2004 Roth et al., 2002). Indeed, increased abdominal adiposity is one of a cluster of factors that are used in the diagnosis of metabolic syndrome. Abdominal tissue in the trunk occurs in several compartments, including subcutaneous and intraperitoneal or visceral fat. Visceral fat in particular appears to contribute to perturbed fuel metabolism by at least two mechanisms. First, hormones and free fatty acids released from visceral fat are released into the portal circulation and impact directly on metabolism of the liver. Second, the visceral adipose depot produces a different spectrum of adipocytokines than that produced by subcutaneous fat (Kershaw and Flier, 2004). 

For example, once in sy.stemic circulation, the plasma pH of 7.4 will be one of the determinants of whether the drug will lend to remain in the aqueous environment of the blood nr partition across lipid membranes into hepatic tissue to he metabolized, into the kidney for excretion, into ii.ssue depots, or to the receptor tissue. A useful exercise is to culculalc cither the conj. ba.se / acid ratio using the Henderson-Has-sclbalch equation (Eq. 2-11) or percent ionization for ephed-rinc (pK , 9.6 Bq. 2-14) and indomclhacin (pK 4.. i 2-... 

Skeletal muscle is a major component of body tissue and accounts for 40-50% of the body weight. Skeletal tissue is composed of specialized striated cells, which function to convert chemical energy to mechanical work. Skeletal muscle plays a central role in body metabolism and serves as a source of body heat and a storage depot for energy-rich compounds, protein, and intracellular ions (e.g., potassium). It also contains up to 80% of the body water content. In contrast to cardiac and smooth visceral muscle tissue, skeletal muscle is under voluntary control. 

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