Drug-nutrient interactions最新文献

The effects on antipyrine metabolism of two levels of carbohydrate, fed intravenously as the sole source of nutrition, were compared. After a 36-hour baseline period during which they received 5% dextrose, 440 kcal per day, intravenously, 8 healthy men were administered 2 sequential intravenous nutritional regimens for 3 days each. One regimen consisted of dextrose 8.1 kcal per kg per day and the other 30.7 kcal per kg per day. The order of the 2 regimens was randomized. Antipyrine metabolism was studied on the last day of each nutritional regimen. Antipyrine kinetics were not influenced by level of carbohydrate intake. Our study indicates that in humans carbohydrate does not by itself have an effect on oxidative drug-metabolizing capacity.

The phospholipid polar head group composition of LM cell plasma membranes was nutritionally altered by choline analogue supplementation. Phosphatidylcholine (PC), normally 60% of total phospholipid, was depleted by 60 to 90% in membranes from cells cultured with N, N'-dimethylethanolamine (DME), N-monomethylethanolamine (ME), and ethanolamine (E). Enrichment of LM cell membranes with choline analogues, such as DME-, ME-, and E-containing phospholipids, decreased the transport of [3H]thymidine, [3H]2-deoxy-D-glucose, and [14C]3-O-methylglucose. Conversely, no change in the transport of [3H] uridine or [14C]aminoisobutyric acid was observed. The toxicity of antineoplastic drugs such as 5-fluorouracil, but not daunorubicin, doxorubicin, or methotrexate, was enhanced threefold in cells enriched with phospholipid containing choline or DME as compared to ME or E. Arrhenius plots of Na+-K+-ATPase activity demonstrated a characteristic temperature at 29 degrees C in plasma membranes from choline-fed cells, while those from analogue-fed cells showed an additional break at 20 degrees C and had higher energies of activation below this temperature. In addition, choline analogue supplementation altered the protein composition of the plasma membrane. The results reported herein demonstrate that nutritional alteration of LM fibroblast plasma membrane phospholipid polar head group composition affects several transport processes and toxicity of some anticancer drugs.

The effect of aluminum injection on the hepatic mixed function oxidase was examined in male Wistar rats. A cannula was surgically implanted in both the control and aluminum treated animals to provide a common port for aluminum injection. In addition, the control animals were pair-fed to the aluminum treated animals. The treated animals accumulated aluminum at about 0.1 mg/gm dry weight of liver/day. At 14 days, the cytochrome P-450 was decreased 20%, but the other components, cytochrome b5 and cytochrome reductases, were unchanged. By day 21 both cytochrome P-450 and cytochrome b5 were reduced 25%. Although NADPH cytochrome c reductase was not affected, the other flavoprotein, NADH cytochrome c reductase, was reduced. Drug metabolism, O-demethylation of p-nitroanisole and p-hydroxylation of aniline, was not affected at 14 days. However, at 21 days O-demethylation was not affected, but aniline hydroxylation was decreased, indicating an affect of aluminum on a specific isoenzyme of cytochrome P-450. Uniquely, the nonactivated glucuronyl transferase activity was fourfold greater in the aluminum treated animals. The increase was greater than cation activation and was similar to the detergent activated activity. Thus, aluminum infusion does produce specific alterations in microsomal function, including drug metabolism and conjugation.

Ethanol was orally administered to seven normal volunteers after three dietary control periods. Diet cycle I was high in protein and calories, cycle II was high in protein but hypocaloric, and cycle III was a combined low-protein, hypocaloric diet. Ethanol elimination was significantly altered by the changes in macronutrients. All volunteers demonstrated diminished ethanol clearance while consuming the hypocaloric diets, and further reduction was seen with an inadequate protein intake. A marked dietary influence on ethanol clearance has been demonstrated in normal male volunteers who have not been exposed to previous ethanol consumption.

Enhanced urinary excretion of vitamins induced by drugs is a major factor in development of vitamin deficiencies. In addition to increasing urinary excretion, drugs can induce vitamin deficiencies by altering their intestinal absorption, transport, storage, and/or metabolic conversions. Aside from drugs, other factors known to influence urinary excretion of vitamins include the level of the vitamin in the diet, the degree of tissue saturation of the vitamin, and the extent of protein binding of the vitamin. Alterations in various aspects of flavin metabolism have been observed following administration of certain drugs, namely, antimalarial, antimicrobial, anticancer, and some tricyclic antidepressant and antipsychotic agents. Of these drugs, boric acid and its derivatives as well as the antipsychotic agent, chlorpromazine, have been shown to promote riboflavinuria in both animals and man. Boric acid complexes with the polyhydroxyl ribitol side chain of riboflavin and greatly increases its water solubility. Individuals who have accidentally consumed boric acid or one of its derivatives excrete high levels of riboflavin within the first 24 to 48 hours following ingestion. The phenothiazine ring of chlorpromazine and the isoalloxazine ring of riboflavin have a number of structural features in common and have been shown to form a molecular complex in vitro. In animals treated for a 3- and 7-week period with chlorpromazine, urinary levels of riboflavin are twice that of pair-fed, saline-treated animals. Recent studies have extended these findings to humans. The administration of certain agents, either therapeutic or toxic, which enhance urinary riboflavin excretion may be of particular concern for high-risk patients who are already nutritionally compromised because of illness or disease.

This study was designed to test the hypothesis that chlorthalidone, a diuretic used to treat hypertension, depletes body zinc enough to interfere with testosterone production and thereby cause sexual dysfunction. Serum and hair zinc, serum testosterone, and sexual function were measured in 19 middle-aged hypertensive men who had been taking chlorthalidone in average daily doses of between 11 and 50 mg per day for at least 6 months, and a control group of 31 unmedicated middle-aged normotensive men. Although the medicated group had a higher incidence of sexual dysfunction (42% as compared to 16% in the control group), use of chlorthalidone did not significantly affect serum testosterone levels. When other variables were controlled for, medicated men had significantly higher serum zinc levels, and men on the highest dosage of chlorthalidone had higher hair zinc levels than all other men. There was no significant correlation between hair zinc, serum zinc, testosterone, and sexual function. Serum zinc decreased significantly with age (p = 0.043) and with ethanol intake after controlling for age (p = 0.032). Sexual dysfunction occurred more often in older men (p = 0.002). In the unmedicated controls, prevalence of dysfunction increased slightly with increasing serum potassium levels.

The effect of chronic ethanol ingestion on fecal and urinary excretion of calcium and magnesium was determined in male rats. The rats were given either 30% ethanol in drinking water and Purina Rat Chow ad libitum (alcohol group) or were pair-fed to the alcohol group, with starch substituted isocalorically for ethanol (pair-fed group). The animals were housed individually in metabolic cages and urine and feces collection was carried out over a period of ten days. Alcohol feeding slightly decreased and pair-feeding slightly increased body weight over the ten-day period, but the differences in body weights were not statistically significant. The fecal calcium excretion was significantly higher and the fecal magnesium excretion was significantly lower in the alcohol group than in the pair-fed controls. The urinary losses of calcium and magnesium were not significantly affected by alcohol intake. The results indicate that chronic administration of alcohol to rats in their drinking water as a sole source of fluid increases fecal calcium excretion, which could result in calcium depletion.

Use of oral neomycin as a hypocholesterolemic agent was found to decrease plasma alpha tocopherol levels during a 9-month, randomized, crossover placebo-controlled clinical trial with controlled diet. Pooled data from each treatment sequence showed a placebo alpha-tocopherol level of 1,896 +/- 643 micrograms/dl, and a neomycin alpha-tocopherol concentration of 1,449 +/- 451 micrograms/dl (p less than .01). When all subjects were on neomycin simultaneously, the level increased to 1,665 +/- 614 micrograms/dl (p less than .05 from placebo). Normal plasma alpha-tocopherol ranges from 400-1,000 micrograms/dl. Neomycin treatment reduces but does not normalize elevated levels of alpha-tocopherol found in Type II hyperlipoproteinemia.

Dietary polyunsaturated fatty acids enhance activation of constitutive and induced forms of enzymes of endoplasmic reticulum responsible for drug and carcinogen metabolism. The current report demonstrates that diets containing 10% or 20% refined menhaden fish oil that contains high concentrations of omega-3 fatty acids also supports these enzymes in a manner similar to that of oils that contain high concentrations of the omega-6 fatty acid linoleate. Cytosolic glutathione S-transferase was unaffected by dietary menhaden oil. However, ingestion of increasing concentrations of menhaden oil increased hepatic microsomal cytochrome P-450 content and the apparent Vmax for ethylmorphine N-demethylase, N-nitrosodimethylamine (DMN) N-demethylase, and benzo(a)pyrene [B(a)P] hydroxylase. Feeding menhaden oil increased the Km for ethylmorphine N-demethylase, and decreased Km's for DMN N-demethylase and B(a)P hydroxylase. Phenobarbital induced glutathione S-transferase activity only in rats fed 10% or 20% menhaden oil. Ethylmorphine N-demethylase was induced by only 25% by phenobarbital in rats refed the fat-free diet compared to 128% in rats refed the 20% menhaden oil. In contrast, DMN N-demethylase was induced only in rats fed the fat-free diet. B(a)P hydroxylase was induced in all rats regardless of the level of dietary fat. The specific activity of cytochrome P-450 for the metabolism of DMN and B(a)P, however, was significantly reduced in menhaden oil-fed animals by phenobarbital. This coupled with the increased Km for these reactions may have significant effects on the in vivo activation of these carcinogens in animals fed menhaden oil and subjected to dietary inducers of the mixed function oxidases.

Diphenolic laxatives are known to alter nutrient absorption and secretion in the small and large intestine. We have studied the effect of 0.75 mM bisacodyl on sugar transport in isolated chicken intestinal epithelial cells. Results show that (1) bisacodyl inhibits Na+-dependent alpha-methyl-glucoside (alpha-MG) accumulation by 45% after 40-minute incubation. (2) The drug reduces initial (1 minute) alpha-MG influx by 60%. This effect is much lower than that exerted by 0.15 mM phlorizin (90% inhibition). (3) Bisacodyl also reduces Na+-independent sugar flux through the basolateral membrane since initial 2-deoxy-glucose influx is reduced 67% by the drug. The effect of the drug on this pathway is lower than that exerted by theophylline (7.5 mM). The addition of bisacodyl or theophylline (plus 20 microM phlorizin to inhibit the apical sugar transport system) to cells preloaded with 3-oxy-methyl-glucose allowed calculation of the initial sugar efflux rate. This was found to be lower after theophylline addition than after the addition of bisacodyl, thus confirming that bisacodyl exerts an incomplete inhibition of the Na+-independent sugar transport system. It is concluded that the direct effects of bisacodyl on both apical and basolateral sugar transport pathways may explain in part the inhibitory effects of the drug on the intestinal absorption of sugars.