Chromium is an essential trace mineral required for carbohydrate and lipid metabolism in rats as well as humans (Mertz 1993). In the United States, chromium content of many self-selected diets is less than 50 µg/d (Anderson and Kozlovsky 1985). Some elderly persons may be at risk of chromium depletion because of decreased food intake due to decreased energy needs and reduced access to a variety of foods (Nordstrom 1982) as well as their altered metabolism due to aging (Nordstrom 1982, Offenbacher 1992).

Drug-nutrient interactions are another concern for elderly persons. Because of the extensive use of over-the-counter as well as prescribed medications, the elderly are particularly at risk for drug-nutrient interactions (Roe 1986). Davis et al. (1995) showed that antacids reduced ⁵¹Cr absorption in rats. In elderly patients, mineral depletion may be the most common example of drug-induced nutritional deficiencies (Roe 1986). Because mechanisms of chromium absorption and metabolism have not been clarified, there is concern regarding impaired chromium status with the use of over-the-counter drugs.

On the other hand, Davis et al. (1995) showed that aspirin, a nonsteroidal antiinflammatory drug (NSAID)⁶ and prostaglandin inhibitor, markedly enhanced absorption, tissue retention and urinary excretion of ⁵¹Cr. Aspirin and indomethacin, another NSAID, are used commonly by elderly persons in the treatment of arthritis.

The gastrointestinal mucosa produces a relatively large quantity of prostaglandins, which affect a number of gastric as well as intestinal functions (Robert 1979). Both indomethacin and aspirin dose-dependently inhibit prostaglandin synthesis and induce gastrointestinal mucosal damage, including ulcers in experimental animals (Kauffman 1989, Miller 1983, Rainsford and Willis 1982, Takeuchi et al. 1986c) and humans (Johansson et al. 1980, Redfern et al. 1987). Gastrointestinal prostaglandins, including prostacyclin (PGI₂), dimethylprostaglandin E₂ (dmPGE₂) and misoprostol, protect the gastrointestinal mucosa against NSAID-induced mucosal damage (Balint and Varro 1989, Brand et al. 1985, Graham et al. 1988, Leung et al. 1989, Nylander et al. 1995, Robert 1979, Robert et al. 1968). The mechanism by which prostaglandins protect gastrointestinal mucosa is still not fully understood, but inhibition of cyclooxygenase activity reduces mucus and bicarbonate secretion (Kauffman 1989, Takeuchi et al. 1986c) and gastrointestinal cytoprotection (Miller 1983).

The effects of prostaglandins on mineral metabolism have not been studied extensively, but some researchers suggest that prostaglandins have a role in the absorption of minerals such as zinc (Song and Adham 1978, 1979), calcium (Johansson et al. 1980) and chromium (Davis et al. 1995). Song and Adham (1979) noted that indomethacin-injected rats had less ⁶⁵Zn (from a duodenal dose) in their internal organs than did controls. Johansson et al. (1980) reported that when indomethacin was used three times daily at 25- or 50-mg doses in the treatment of rheumatic diseases, a significant reduction in serum calcium was found. Their results suggest that prostaglandins may have a role in calcium homeostasis in humans.

For chromium, Davis et al. (1995) showed that absorption, tissue retention and urinary excretion of ⁵¹Cr were significantly higher in animals dosed orally with aspirin than in control animals. They suggested that aspirin, a NSAID, inhibited endogenous prostaglandin synthesis and enhanced chromium absorption. Effects of gastrointestinal prostaglandins on chromium have not been studied.

One objective of the present study was to inhibit the synthesis of endogenous gastrointestinal prostaglandins and measure ⁵¹Cr absorption, tissue distribution and urinary excretion. A second objective was to evaluate the effects of supplemental prostaglandin analogues or PGI₂ on ⁵¹Cr.

MATERIALS AND METHODS

Twenty-four rats were injected intraperitoneally with 5 mg indomethacin/kg body wt suspended in 0.15 mol/L saline containing 3.82 mmol/L Tween-80; the other 24 rats were injected with the same volume of 0.15 mol/L saline containing 3.82 mmol/L Tween-80 without indomethacin (placebo). Thirty minutes later, the rats were intubated and dosed with one of four different treatments: control (7.64 mmol/L Tween-80 suspended in 0.48 mol/L ethanol and 0.15 mol/L NaCl used for the other drugs), 50 µg/kg body wt of misoprostol [a prostaglandin E₁ (PGE₁) analogue], 7.5 µg/kg body wt of 16,16-dmPGE₂ [a prostaglandin E₂ (PGE₂) analogue] or 20 µg/kg body wt of PGI₂. Immediately after intubation, the rats were given an oral dose of 3.7 mBq of ⁵¹CrCl₃ (0.18 µg of chromium in 50 µL of 0.02 mol/L HCl) by micropipette.

The principal diluent for all intubated drugs was a suspension of 7.64 mol/L Tween-80 in 0.15 mmol/L NaCl. Ethanol concentrations were kept below 0.48 mol/L for all drugs but varied somewhat due to differences in solubility. The control was prepared by adding 0.48 mol/L ethanol to the 7.64 mmol/L Tween-80 suspension in 0.15 mol/L NaCl used for the other drugs.

Misoprostol was prepared for dosing by adding 20 mL of ethanol to 100 µg of ground tablet and diluting in 0.15 mol/L NaCl containing 7.64 mmol/L Tween-80. Rats were given 50 µg misoprostol/kg body wt by gastric intubation.

The dmPGE₂ was received as 1 mg in 100 µL of methyl acetate and was diluted with 100 µL of 95% ethanol. Immediately before gastric intubation, the dmPGE₂ was diluted to a final concentration of 1.5 mg/L in 0.15 mol/L NaCl containing 7.64 mmol/L Tween-80. Rats were intubated with 7.5 µg dmPGE₂/kg body wt.

Prostacyclin was prepared for dosing by adding 200 µL of 95% ethanol to 1 mg of PGI₂. The PGI₂ was diluted to a final concentration of 10 mg/L in 7.64 mmol Tween-80 in 0.15 mol/L NaCl. Rats were intubated with 20 µg PGI₂/kg body wt.

Table 1. Tissue 51Cr after pretreatment with indomethacin or placebo, at 6 h after dosing with control, misoprostol, dimethylprostaglandin E2 (dmPGE2) or prostacyclin (PGI2) in rats1 [View Table]

Calculation of total ⁵¹Cr in blood was performed assuming blood was 7% of body weight (Harkness and Wagner 1983). Data are expressed as a percentage of the intubated chromium dose. Samples of the dose were counted each day with tissue samples to allow correction for decay of the ⁵¹Cr.

RESULTS

The control group had higher ⁵¹Cr absorption into blood than the groups that received misoprostol (P < 0.03) or dmPGE₂ (P < 0.0001) (Fig. 2). The value for the group dosed with dmPGE₂ was lower (P < 0.03) than for all other treatment groups.

In tissues of indomethacin-pretreated rats, retention of ⁵¹Cr was greater (P < 0.03) in all tissues except lung, compared with the placebo group, which was not pretreated with indomethacin (Table 1). Most of the ⁵¹Cr retained in tissues was in liver and kidney.

When drugs were compared, retention of ⁵¹Cr was reduced significantly (P < 0.05) by dmPGE₂ compared with all other groups in liver, kidney, spleen, testes and bone (Table 1). Tissue retentions in control, misoprostol- and PGI₂-treated groups were not significantly different. In heart, ⁵¹Cr retention in the dmPGE₂-treated group was significantly lower than in the control and misoprostol groups but not lower than in the PGI₂-treated group. In the lung and pancreas, ⁵¹Cr retention was not significantly affected by the administered prostaglandin analogues or by prostacyclin.

The total cumulative urinary excretion of ⁵¹Cr was higher (P < 0.05) in indomethacin-treated than in placebo-treated rats (0.44 vs. 0.21% of ⁵¹Cr dose). Urinary excretion of ⁵¹Cr at 4 h tended to be higher (P < 0.06) in indomethacin-treated rats. The significance level for the effect of drugs on urinary excretion of ⁵¹Cr was 0.09. The group treated with dmPGE₂ tended (P < 0.09) to have lower urinary ⁵¹Cr excretion than all other groups (Fig. 3).

DISCUSSION

Some studies have shown that a variety of prostaglandins and analogues reduce gastrointestinal side effects associated with NSAID, including indomethacin, when taken together (Johansson et al. 1980). In the small bowel, increases in PGE₂ generation were correlated with decreases in permeability (Gerstle et al. 1994, Nylander et al. 1995). In the present study, oral dosing with dmPGE₂ significantly decreased ⁵¹Cr absorption, compared with control rats that received no exogenous prostaglandins or analogues. Other investigators found that administration of dmPGE₂ (30 µg/kg) significantly increased HCO₃ output in rats dosed with 5 mg indomethacin/kg (Takeuchi et al. 1988). Likewise, dmPGE₂ doses of 5 µg/kg (Leung et al. 1989) and 10-30 µg/kg (Takeuchi et al. 1986b) increased mucosal alkaline secretion in rats. Takeuchi and co-workers (1986a) suggested that endogenous prostaglandins have a role in maintaining acid-neutralizing capacity in the duodenum. Because indomethacin not only restricts blood flow and inhibits formation of mucus but also leaves the surface exposed to acid, this acidic environment may further promote chromium absorption. Chromium is poorly absorbed from alkaline environments (Mertz 1969), which may contribute to the decreased absorption seen in this study with PGE₂ administration. Increased cytoprotection by prostaglandins (Miller 1983) also may have reduced ⁵¹Cr absorption.

Misoprostol, a PGE₁ analogue, inhibits gastric acid secretion in dogs at doses of 10-30 µg/kg (Dajani et al. 1976) and in humans (Brand et al. 1985). In the present study, ⁵¹Cr in blood following dosing with 50 µg/kg of misoprostol was significantly lower than in the control group but significantly higher than in the group dosed with 7.5 µg/kg body wt of dmPGE₂. Rats dosed with PGI₂ also had more ⁵¹Cr in blood than rats dosed with dmPGE₂. Neither PGE₁ analogue or PGI₂ significantly affected urinary excretion or tissue concentrations of ⁵¹Cr. Thus at the doses used, dmPGE₂ had the greatest inhibitory effect on ⁵¹Cr absorption and retention.

In summary, enhanced ⁵¹Cr absorption seen with indomethacin pretreatment may be mediated by an increase in mucosal permeability, by the inhibition of gastrointestinal prostaglandin synthesis, or by the presence of a more acidic luminal environment. These results suggest that directly or indirectly prostaglandins may influence chromium absorption.