Tissue metabolism

In humans, thiamine is both actively and passively absorbed to a limited level in the intestines, is transported as the free vitamin, is then taken up in actively metabolizing tissues, and is converted to the phosphate esters via ubiquitous thiamine kinases. During thiamine deficiency all tissues stores are readily mobilhed. Because depletion of thiamine levels in erythrocytes parallels that of other tissues, erythrocyte thiamine levels ate used to quantitate severity of the deficiency. As deficiency progresses, thiamine becomes indetectable in the urine, the primary excretory route for this vitamin and its metaboHtes. Six major metaboHtes, of more than 20 total, have been characterized from human urine, including thiamine fragments (7,8), and the corresponding carboxyHc acids (1,37,38). 

Rybicka, K. IC, 1996. Glycosomes—The organelles of glycogen metabolism. Tissue and Cell 28 253-265. 

PBPK and classical pharmacokinetic models both have valid applications in lead risk assessment. Both approaches can incorporate capacity-limited or nonlinear kinetic behavior in parameter estimates. An advantage of classical pharmacokinetic models is that, because the kinetic characteristics of the compartments of which they are composed are not constrained, a best possible fit to empirical data can be arrived at by varying the values of the parameters (O Flaherty 1987). However, such models are not readily extrapolated to other species because the parameters do not have precise physiological correlates. Compartmental models developed to date also do not simulate changes in bone metabolism, tissue volumes, blood flow rates, and enzyme activities associated with pregnancy, adverse nutritional states, aging, or osteoporotic diseases. Therefore, extrapolation of classical compartmental model simulations... 

Feroz, M. and M.A.Q. Khan. 1979a. Metabolism, tissue distribution, and elimination of cw-[14C] chlordane in the tropical freshwater fish Cichlasoma sp. Jour. Agric. Food Chem. 27 1190-1197. 

Hakk H, Larsen G, Bowers J (2004) Metabolism, tissue disposition, and excretion of 1,2-bis (2,4,6-tribromophenoxy)ethane (BTBPE) in male Sprague-Dawley rats. Chemosphere... 

De Buck, S.S., Sinha, V.K., Eenu, L.A., Gilissen, R.A.H.J., Mackie, C.E. and Nijsen, M.J. (2007) The prediction of drug metabolism, tissue distribution, and bioavailability of 50 structurally diverse compounds in rat using mechanism-based absorption, distribution, and metabolism prediction tools. Drug Metabolism and Disposition The Biological Fate of Chemicals, 35, 649-659. 

Another model, which is increasingly being used, is the physiologically based pharmacokinetic model. This uses data on the absorption, distribution, metabolism, tissue sequestration, kinetics, elimination, and mechanism to determine the target dose used for the extrapolation, but it requires extensive data. 

Nutritional status determines effects of therapeutic drugs and recognition of these factors should lead to improved drug therapy. Pharmacokinetics are changed by a person s diet but metabolic tissue and cellular effects are not well understood. Biochemical transformations and enzyme inductions that decrease or increase toxicity of drugs are discussed and numerous examples given. 

Franke C, Brinker G, Pillekamp F, Hoehn M (2000) Probability of metabolic tissue recovery after thrombolytic treatment of experimental stroke a magnetic resonance spectroscopic imaging study in rat brain. J Cereb Blood Flow Metab 20 583-591... 

Although the antibacterial spectrum is similar for many of the sulfas, chemical modifications of the parent molecule have produced compounds with a variety of absorption, metabolism, tissue distribution, and excretion characteristics. Administration is typically oral or by injection. When absorbed, they tend to distribute widely in the body, be metabolized by the liver, and excreted in the urine. Toxic reactions or untoward side effects have been characterized as blood dyscrasias crystal deposition in the kidneys, especially with insufficient urinary output and allergic sensitization. Selection of organisms resistant to the sulfonamides has been observed, but has not been correlated with cross-resistance to other antibiotic families (see Antibacterial AGENTS, SYNTHETIC-SULFONAMIDES). 

Essential oils should always be used in a controlled manner and this usually involves a low concentration reaching the metabolizing tissues. This is consistent... 

In the clinic, esmolol s distribution half-life is 2 min and its elimination half-life is 9 min. Esmolol hydrochloride is rapidly metabolized by hydrolysis of the ester linkage, chiefly by esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase [22]. Its volume of distribution is 3.4 L kg-1, and its total clearance is 285 mL kg-1 min-1, "... which is greater than cardiac output thus the metabolism ofesmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flout [22]. As expected from such a "... high rate of blood-based metabolism, less than 2% of the drug is excreted unchanged in the wind [22]. Within 24 h after infusion, approximately... 

The differences of the metabolic blood parameters after compound administration are calculated with respect to the pre-drug values and against a control group, which has received the vehicle only. The metabolic tissue parameters at the end of the study are assessed between control and treatment group. 

CRITICAL ASSESSEMENT OF THE METHOD The results of metabolic tissue parameters in liver, and muscle must be interpreted carefully, when a hyperinsulinemic-euglycemic glucose clamp study is performed at the end of the treatment period. Under clamp conditions these tissue parameters are mainly influenced by the hyperinsulinemic condition during the clamp study than by the compound s effect itself. 

The cytochome P-450 systems of the steroid producing tissues have many characteristics in common with those of the liver and other xenobiotic-metabolizing tissues. They require NADPH and molecular oxygen, and contain a flavoprotein, NADPH cytochrome P-450 reductase. Unlike the systems in the liver, however, the steroid hydroxylases are associated with both the endoplasmic reticulum and the mitochondria and are quite specific for the different reactions that they catalyze. Thus, adrenal microsomes... 

ANTI HYPERTENSIVES AND HEART FAILURE DRUGS NS AIDs 1 hypotensive effect, especially with indometacin. The effect is variable amongst different ACE inhibitors and NSAIDs, but is most notable between captopril and indometacin NSAIDs cause sodium and water retention and raise BP by inhibiting vasodilating renal prostaglandins. ACE inhibitors metabolize tissue kinins (e.g. bradykinin) and this may be the basis for indometacin attenuating hypotensive effect of captopril Monitor BP at least weekly until stable. Avoid co administering indometacin with captopril... 

Metabolism studies of PCDEs in rats and fish have shown that PCDEs are metabolized more and excreted faster in rats compared to fish. When metabolism, tissue distribution and excretion of PCDEs was studied in male Sprague-Dawley rats with PCDE 99 (2,2, 4,4, 5-pentaCDE), 55% of PCDE 99 orally fed was excreted in feces in seven days and 64% of PCDE 99 was excreted unchanged [34]. Half-lives of hepta- through nonaCDEs in various tissues of rat have ranged between 5.7 days and 13.4 days [108]. 

Often the data cannot be related quantitatively to that obtained from studies with more highly organised systems, not only because of the altered circumstances of the adenylate cyclase (e.g. dilution effects, absence of endogenous inhibitors or activators), but also because of possible differences in the way the hormone is handled (e.g. metabolism, tissue uptake). As a rule, adenylate cyclase activity in broken cell preparations is less sensitive to hormonal stimulation than activity in intact cells [94], and guanylate cyclase activity does not respond to agents which increase the cyclic GMP level in intact cells [29]. 

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