Nonhepatic metabolism

One of the drugs that is metabolized in the blood is succinylcholine, a muscle relaxant that is hydrolyzed by the pseudocholinesterase of liver and plasma to succinylmonocholine. The short duration of action of succinylmonocholine (5 min) is due to its rapid hydrolysis in plasma. Patients 

The lung is involved in both the activation and inactivation of numerous physiologic and pharmacologic substances. For example, angiotensin I is converted to angiotensin II in the lung. 

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Other groups also made attempts to separate local and systemic effects by integrating moieties susceptible to rapid, nonhepatic metabolism within the corticosteroid structure. One of the more successful attempts explored 17a-(alkoxycarbonyl)alkanoate analogs (35) of clobetasol propionate (144). Again, this can be considered as a hypothetical inactive metabolite—based approach, and a corresponding metabolite (35)(n. = 2, R = H) has indeed been shown to be inactive. Esters that were susceptible to rapid hydrolysis exhibited good separation of topical anti-inflammatory to systemic activity. The study also indicated the existence of an optimal volume for the 17a side chain. For example, the methyl succinate derivative (35) (/i = 2, R = methyl) showed as potent topical anti-inflammatory activity as clobetasol propionate, but a dramatically reduced thymolytic activity. Therefore, the cor-... 

Renal elimination of unchanged drug accounts for 66% of drug clearance, and the dose should be adjusted for impaired renal function. The role of therapeutic drag monitoring is unknown. It has linear pharmacokinetics and is metabolized in blood by nonhepatic enzymatic hydrolysis. 

Although elevated levels of cholesterol and LDL in human plasma are linked to an increased incidence of cardiovascular disease, recent data have shown that an increase in concentration of HDL in plasma is correlated with a lowered risk of coronary artery disease. Why does an elevated HDL level in plasma appear to protect against cardiovascular disease, whereas an elevated LDL level seems to cause this disease The answer to this question is not known. An explanation currently favored is that HDL functions in the removal of cholesterol from nonhepatic tissues and the return of cholesterol to the liver, where it is metabolized and secreted. The net effect would be a decrease in the amount of plasma cholesterol available for deposit in arteries (see... 

From 1978 to 1985 renewed interest in tryptophan metabolism via the kynurenine-niacin pathway was generated by the findings of Hayaishi et al. and others of a second enzyme, namely, indoleamine-2,3-dioxygenase (IDO).2 3 This enzyme was found to be present in several nonhepatic tissues (lung, intestine, brain, and epididymis) and cells (blood monocytes, macrophages, and eosinophils). The enzyme normally has very low activity but is induced to very high activity by stimulation of immune systems with interferon-y1-8 or interleukin-2 (cytokines).9 Thus, inflammatory processes, infections, and immune stimulation that induce interferon-y could lead to... 

Plasma tryptophan concentration is a function of dietary tryptophan intake as well as the extent of removal of tryptophan from blood by tissues. The liver is the main organ influencing plasma tryptophan concentration since it actively metabolizes tryptophan while nonhepatic tissues have only relatively limited ability to act in this manner. Following a meal, in the liver, tryptophan stimulates hepatic tryptophan oxygenase activity, which affects tryptophan catabolism and determines how much tryptophan enters the general circulation. 

Cytochrome P-450 is also known to function in nonhepatic sites. It has been found in the mucosa of the intestine, in kidneys and in the adrenal cortex. It is believed to hydroxylate endogenous steroids as well as to metabolize some drugs in the cortex. 

In essential fructosuria, fructose cannot be converted to fructose 1-phosphate. This condition is benign because no toxic metabolites of fructose accumulate in the liver, and the patient remains nearly asymptomatic. Some of the ingested fructose is slowly phosphorylated by hexokinase in nonhepatic tissues and metabolized by glycolysis, and some appears in the urine. There is no renal threshold for fructose the appearance of fructose in the urine (fructosuria) does not require a high fructose concentration in the blood. 

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