Balance study, human

Following inhalation exposure to trichloroethylene in humans, the unmetabolized parent compound is exhaled, whereas its metabolites are primarily eliminated in the urine. Excretion of trichloroethylene in the bile apparently represents a minor pathway of elimination. Balance studies in humans have shown that following single or sequential daily exposures of 50-380 ppm trichloroethylene, 11% and 2% of the dose was eliminated unchanged and as trichloroethanol, respectively, in the lungs 58% was eliminated as urinary metabolites and approximately 30% was unaccounted for (Monster et al. 1976, 1979). Exhaled air contained notable concentrations of trichloroethylene 18 hours after exposure ended because of the relatively long half-life for elimination of trichloroethylene from the adipose tissue (i.e., 3.5-5 hours) compared to other tissues (Fernandez et al. 1977 Monster et al. 1979). 

Review of studies on the effect of oxalic acid on calcium bioavailability in rats and in humans indicates that most of the research was done between 1930 and 1950. Decreased availability of calcium in young rats was reported when spinach containing oxalic acid was fed with low calcium diets. The extent of the effect of oxalic acid on calcium availability was shown to be related to levels of calcium and oxalic acid, as well as the presence of vitamin D in the diet. In human studies there was generally no effect of oxalic acid on calcium balance however, in a few studies decreased calcium balances were reported. There is recent evidence that oxalic acid consumed along with a moderately high level of fiber intake may have adverse effects on calcium balance of human subjects. 

Since the early 1970 s, research has been directed at identifying the mechanism by which the calciuria is induced. Attention was given first to the question of whether the elevated urinary calcium excretion was caused by an increase in the intestinal absorption of calcium. Results of calcium balance studies in human subjects showed that protein ingestion either had no effect on calcium absorption (4) or that the effect was insufficient to account for the calciuria (5j. Consequently, negative calcium balance is a frequent observation in human studies when high protein diets are fed, and this situation is not improved by high calcium intakes (4 ). 

Most of the forementioned studies which examined the influence of various dietary fiber on the bioavailability of calcium by human subjects have depended upon the comparative measurements of calcium content of diets and calcium contents of stools and urine. As reviewed by Allen (3), calcium balance studies have distinct limitations relative to accuracy and precision. However, their ease of application and cost, laboratory equipment requirements, and real (or perceived) safety in comparison to available radioactive or stable isotope methods continue to make their use popular. In calcium balance studies, calcium absorption is assumed to be the difference between calcium excretion in the feces and calcium intake. Usually this is expressed as a percent of the calcium intake. This method assumes that all fecal calcium loss is unabsorbed dietary calcium which is, of course, untrue since appreciable amounts of calcium from the body are lost via the intestinal route through the biliary tract. Hence, calcium absorption by this method may underestimate absorption of dietary calcium but is useful for comparative purposes. It has been estimated that bile salts may contribute about 100 g calcium/day to the intestinal calcium contents. Bile salt calcium has been found to be more efficiently absorbed through the intestinal mucosa than is dietary calcium (20) but less so by other investigators (21). 

The permeability of the drug substance can be determined by different approaches such as pharmacokinetic studies in humans (fraction absorbed or mass balance studies) or intestinal permeability studies (in vivo intestinal perfusion studies in humans or suitable animal models or in vitro permeation studies using excised intestinal tissue or epithelial cell culture monolayers like CaCo-2 cell line). In order to avoid misclassification of a drug subject to efflux transporters such as P-glycoprotein, functional expression of such proteins should be investigated. Low- and high-permeability model... 

The steady-state volume of distribution is 12 1/kg. Donepezil hydrochloride is approximately 96% bound to human plasma proteins. The distribution of donepezil hydrochloride in various body tissues has not been definitively studied. However, in a mass balance study conducted in healthy male volunteers, 240 h after the administration of a single 5 mg dose of 14C-labeled donepezil hydrochloride, approximately 28% of the label remained unrecovered. This suggests that donepezil and/or its metabolites may persist in the body for more than 10 days. 

Roffey, S. J., Obach, R. S Gedge, J. I., Smith, D. A. What Is the Objective of the Mass Balance Study A Retrospective Analysis of Data in Animal and Human Excretion Studies Employing Radiolabeled Drugs. Drug Metab. Rev. 2007, 39, 17—43. 

Mean daily balances (excluding loss via hair and sweat) determined from long- term balance studies of four adult subjects ranged from a negative balance of 800 pg to a positive balance of 890 pg (Tipton et al. 1966, 1969). Based on data from these studies, Schroeder (1970) estimated that human daily intake from food (1,160 pg), water (80 pg), and air (10 pg) would be approximately 1,250p... 

Accepted as basis for human mass balance studies (dosimetry calculations)... 

Design and conduct mass balance study in human volunteers using an appropriately labeled drug candidate. 

The first manganese balance study in humans was conducted in 1934 by Everson and Daniels (16) who studied children ages 3 to 5 years (Table 1). The children were fed... 

The balance study technique has been used In all of these studies. Although there are difficulties and certain problems with balance studies, nutrition researchers have not yet found a reasonable and realistic alternative to estimate nutrient needs of human subjects. Continued development and Increased sophistication of methods and analytical techniques may provide alternatives In the future, but these are not clearly available at the present time. 

Fiber components can bind zinc and other minerals, possibly rendering the minerals unavailable for absorption by the animal body (1, 2,. The effect of fiber on zinc balance of human subjects was reviewed previously (4) and appears to be related to level and kind of fiber, level of zinc, other components of the diet, and length of study period. One of the dietary components which may affect zinc availability is oxalic acid. 

Studies on the effect of oxalic acid in spinach on calcium balance in humans have shown a small decrease or no effect on calcium balance (12). However, when subjects were given test meals of either Swiss chard (13) or amaranth (, 1, which are rich in oxalic acid, urinary excretion of calcium indicated that the absorption of calcium from these sources was less than that of an equal amount of calcium from milk. Absorption of calcium from milk was also reduced when given along with amaranth (14). 

Since we did not find adverse effects on zinc balance by the higher fiber diet containing spinach until the fourth week of study 3, balance studies should be carried out for longer periods of time to determine if negative zinc balances persist. Perhaps in the earlier studies on effects of spinach on calcium balance of human subjects, more definitive effects would have been noted if the spinach had been fed along with a higher fiber diet. Length of study period is also a likely factor, as some of the studies were carried out for less than 2 weeks. 

We conducted a human metabolic balance study to test the concept of dietary phytate/zinc molar ratio as a predictor of zinc bioavailability to humans. Using unaltered or enzymatically dephytinlzed wheat bran with ordinary foods we attained phytate zinc molar ratios of about 1 and 12 with relatively high intakes of dietary fiber in the menus and found no difference in zinc balance. Retrospectively, the result may be qualified on the basis of the magnitude of the zinc Intake and possible adaptive or homestatic responses over the period of the study. A second study was then conducted and a wider range of phytate/zinc molar ratio was provided than in the first study. We will briefly outline the first study, give a progress report on the second study and, with some information on phytate intakes obtained by our laboratory, discuss the nutritional implication. 

Although the balance results indicate that in human diets a phytate/zinc molar ratio of 12 is not a deterrent to adequate zinc nutriture in adult men, qualifications as discussed above raise questions in interpreting the practical application. We have pursued two questions (1) What is the molar ratio of phytate/ zinc in our typical diets (2) What would be the effect of lower zinc intakes in a metabolic balance study with phytate/zinc molar ratio as the variable Part of question 1 has been completed, but only preliminary Information is available on question 2. 

The authors thank Priscilla Steel, Sheryl Cottrell and staff of the Human Study Facility, BHNRC Dr. Phylis Moser and Taryn Moy, College of Human Ecology, University of Maryland, College Park, and David Hill, VMNL, BHNRC for their cooperative efforts toward the metabolic balance studies. 

Methods for studying zinc bioavailability in humans include metabolic balance studies, radioisotopic techniques, stable isotope techniques, circulating zinc response, and perfusion techniques. These methods of bioavailability, along with other zinc-related studies, also are covered in detail. 

Rosdahl H, Ungerstedt U, Jorfeldt L, Henriksson J (1993) Interstitial glucose and lactate balance in human skeletal muscle and adipose tissue studied by microdialysis. J Physiol London 471 637-657. 

Several approaches have /been used to determine absorption of trace elements in humans. The most frequently used method has been balance studies, in which the amount of a mineral ingested is compared with the amount eliminated in the feces. However, absorption calculated from total mineral eliminated in fecal collections generally differs greatly from true absorption, since some of the mineral eliminated in the feces is of endogenous origin (1). A number of other difficulties with metabolic balance studies, such as variation in intestinal transit time and inadequate analytical precision, limit their usefulness and often result in conflicting results (2). 

Garza, C., Scrimshaw, N. S., and Young, V R (1977). Human protein requirements A long term metabolic nitrogen balance study in young men to evaluate the 1973 FAO/WHO safe level of egg protein intake. /. Nutr. 107,335-352. 

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