Search

Comparison of Olestra Absorption in Guinea Pigs with Normal and Compromised Gastrointestinal Tracts. Daher, G. C, Lawson, K. D., Long, P. H., Tallmadge, D. H., Boothe, A. D., Vanderploeg, P., and Miller, K. W. (1997). Fundam. Appl. Toxicol. 39, 138-147. Female guinea pigs (12/group) were given a single dose of (I4C)- olestra by gavage after consuming either 3% poligeenan in tap water (Compromised group) or just tap water (Normal group) for 5 weeks. A Sentinel group (N = 2) was given 3% poligeenan for 5 weeks. Ten sentinel animals were killed 1 day before and 10 1 day after the other animals were dosed with (uC)olestra and their gastrointestinal tracts were examined by histology. The Compro- mised and Normal animals were endoscoped just before dosing with (MC)olestra. Urine and feces were collected continuously and CO2 was collected for 7 days after dosing. The samples were ana- lyzed for 14C and urine was also analyzed for (MC)sucrose. Animals (3/group) were killed 1, 3, 7, and 21 days after dosing, and tissues were collected and assayed for MC. Tissue lipids were extracted, fractionated by high-pressure liquid chromatography, and ana- lyzed for (uC)olestra by liquid scintillation. Animals fed poligee- nan showed mucosal edema, congestion, ulceration, and fibrin de- position within the distal colon and rectum. Histology revealed inflammation, epithelial degeneration, and multifocal ulceration of the cecum, distal colon, and rectum. The gastrointestinal muco- sae of nonpoligeenan fed animals were normal. No ( MC)olestra was detected in liver lipids and no (uC)sucrose was found in the urine for any animal in the Normal or Compromised groups, indi- cating that intact olestra was not absorbed. The amount, distribu- tion, and elimination of absorbed I4C did not differ between guinea pigs with normal and compromised gastrointestinal tracts. The poligeenan-treated animals displayed mucosal damage similar to that seen in human inflammatory bowel diseases; therefore, these results suggest that patients with inflammatory bowel conditions will not absorb olestra to any greater extent than normal healthy

A study was conducted in the domestic pig to determine 1 ) whether feeding olestra mixed in the diet exaggerated olestra effects on fat-soluble vitamin status compared with the effects of feeding it in a typical snack food, and 2) whether separating olestra consumption temporally from vitamin consumption affected the influence of olestra on vitamin status. Groups of 10 pigs each, five castrated males and five females, were fed 2.2% (wt/wt) olestra for 4 wk in purified diet that provided 1 time the National Research Council's requirements for swine of all micronutrients. The olestra was either mixed in the purified diet or fed in potato chips. The potato chips were given to the pigs at all three feedings, at the noon feeding only, or between the noon and the evening feedings. A control group was fed the purified diet with no olestra. The effects of olestra on indices of vitamin A, D and E status were from 1.7 to 4.5 times greater when olestra was fed three times daily mixed in the diet than when it was fed three times daily in potato chips. Because the effect of olestra on the status of the fat-soluble vitamins was diminished substantially by feeding the olestra in potato chips, it was not possible to conclude definitively how the temporal separation of olestra and vitamin consumption affected the olestra effect on vitamin status.

The effect of olestra, a zero-calorie fat replacement, on the absorption of dietary fat was determined with a dual-isotope technique in 67 healthy male subjects. After a 30-d adaptation period in which they consumed potato chips which delivered either 10 g/d olestra or 10 g/d triglyceride under free-living conditions, the subjects were housed in a metabolic ward and given 0, 8, 20 or 32 g olestra in potato chips. The chips were eaten as part of a breakfast containing about 38 g of fat, about 0.16 mg of 14 C-triolein, and a nonabsorbable marker, 51 CrCl 3 . Feces were collected for 7 d, and aliquots of the two daily collections containing the highest levels of 51 Cr were oxidized. The CO 2 was collected, and 14 C content was determined by liquid scintillation spectrometry. The fractional absorption of 14 C-triolein was calculated from the average ratios of 14 C/ 51 Cr dosed and measured in the feces. Olestra had a slight but significant dose-response effect on triglyceride absorption: the highest olestra dose (32 g) reduced absorption by 1.2%. This effect is not nutritionally significant with respect to either availability of essential fatty acids or energy intake.

Regional infusion with fluoropyrimidines is useful in the treatment of hepatic metastases. However, the effectiveness of regional infusion is minimized by rapid degradation of 5-fluorouracil (FUra) and 5-fluoro-2′-deoxyuridine (FdUrd) by the liver which limits the availability of drug for anabolism to active metabolites. 5-Benzyloxybenzyluracil (BBU) is a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), the initial enzyme in FUra catabolism (Naguib FMN, el Kouni MH and Cha S, Biochem Pharmacol38: 1471–1480, 1989). The effect of BBU on fluoropyrimidine catabolism in the liver was evaluated using the isolated perfused rat liver (IPRL). BBU infused at 0.35 μM over the course of 1 hr demonstrated no hepatotoxicity as measured by bile flow, O2 uptake and lactate dehydrogenase leakage. The effect of BBU (0.35 μM) on the catabolism of FUra (10 μM) or FdUrd (10 μM) was quantitated by HPLC at 5- or 10-min intervals over a 1-hr period. BBU maximally inhibited FUra catabolism by approximately 83%. Further studies utilizing short-term (20 min) infusion of BBU prior to administration of FUra suggested that the inhibition of DPD was reversible. While FdUrd phosphorolysis was not affected, subsequent catabolism of FUra decreased by 70%. Studies on isolated hepatocytes indicated that the increased FUra level in perfusate resulted from inhibition of FUra catabolism and not from inhibition of FUra transport. The significant inhibition of FUra catabolism suggests that BBU may be useful in modulating regional chemotherapy by these fluoropyrimidines.

This study examined the effect of olestra, a zero-calorie fat replacement, on the absorption of retinyl palmitate in humans. After a 30-d adaptation period during which they consumed 10 g olestra/d in potato chips under free-living conditions, 68 healthy male subjects were housed in a metabolic ward and given a single dose of retinyl palmitate (0.33 RDA) containing a trace amount of 3H-retinyl palmitate with a breakfast that contained 0, 8, 20 or 32 g of olestra and about 38 g of triglyceride. Blood was collected at defined intervals for 48 h and plasma analyzed for 3H-retinyl esters by HPLC and liquid scintillation spectrometry. There was no significant effect on retinyl palmitate absorption as determined from the area under the plasma 3H-retinyl esters concentration-time curve. However, an area under the plasma concentration-time curve in the 32-g olestra group that was 81% (mean value) or 70% (median value) of the area under the curve for the placebo group suggested that olestra may have affected retinyl palmitate absorption. Inclusion or exclusion of 13 high responders did not change the results.

The isolated perfused rat liver was used to examine the hepatic extraction, biliary secretion and effect on bile flow of the 2-fluoro-beta-alanine conjugates of cholic acid and chenodeoxycholic acid. The naturally occurring taurine and glycine conjugates of these bile acids were used for comparisons. The 2-fluoro-beta-alanine conjugates were extracted by the liver to a similar extent as the taurine and glycine conjugates. The biliary secretion rate and increase in bile flow were similar for all the cholic acid conjugates. On the other hand, the maximal biliary secretion rate of the 2-fluoro-beta-alanine conjugate of chenodeoxycholate was similar to that of the glycochenodeoxycholate, but 47% lower than that of taurochenodeoxycholate. In addition, the 2-fluoro-beta-alanine conjugate of chenodeoxycholate produced a decrease in bile flow that was comparable to that observed with the glycochenodeoxycholate (54% vs. 74%), but which was greater than that produced by the taurochenodeoxycholate (12%). In summary, these data demonstrate that the biological properties of the 2-fluoro-beta-alanine conjugates of cholic acid and chenodeoxycholic acid are not markedly different from those of the naturally occurring taurine and glycine conjugates. These data also suggest that the amino acid moiety can influence the biliary secretion and cholestatic properties of chenodeoxycholic acid conjugates.

The pyrimidine antimetabolite drugs consist of base and nucleoside analogues of the naturally occurring pyrimidines uracil, thymine and cytosine. As is typical of antimetabolites, these drugs have a strong structural similarity to endogenous nucleic acid precursors. The structural differences are usually substitutions at one of the carbons in the pyrimidine ring itself or substitutions at on of the hydrogens attached to the ring of the pyrimidine or sugar (ribose or deoxyribose). Despite the differences noted above, these analogues, can still be taken up into cells and then metabolized via anabolic or catabolic pathways used by endogenous pyrimidines. Cytotoxicity results when the antimetabolite either is incorporated in place of the naturally occurring pyrimidine metabolite into a key molecule (such as RNA or DNA) or competes with the naturally occurring pyrimidine metabolite for a critical enzyme. There are four pyrimidine antimetabolites that are currently used extensively in clinical oncology. These include the fluoropyrimidines fluorouracil and fluorodeoxyuridine, and the cytosine analogues, cytosine arabinoside and azacytidine.