Studies of water movement across the gut using oral rehydration solutions in a rat perfusion model

Aim: To measure water influx and efflux, as well as net water, sodium and potassium absorption from a range of oral rehydration solutions (ORS) in which the glucose content had been partially replaced with the amino acid leucine or with food supplements. Methods: A series of in vivo steady-state perfusion studies in normal rat intestine. The oral rehydration solutions contained 60 or 90 mmol/L of sodium. The reference solution used was the World Health Organization (WHO) formula. Results: There was a significant negative correlation between the oral rehydration solution osmolality and net water absorption (r=–0.722, P < 0.05). The highest net water absorption occurred using comminuted chicken supplemented oral rehydration solution containing 60 mmol/L sodium (P < 0.001). This oral rehydration solution also showed a significant increase in the rate of influx of water (P < 0.05) in comparison with the WHO formula containing 60 mmol/L sodium. Conclusion: This work provides further evidence that food-based oral rehydration solutions, including non-vegetable sources, may have a useful role to play in the management of patients with acute diarrhoea.     

Absorption and metabolism of hydrocortisone 21-butyrate, 21-hemisuccinate and hydrocortisone by skin of the rabbit ear during single-pass perfusion

1. Rabbit ear was single-pass perfused with protein-free buffer solution at a rate of 0.02 ml/min per cm² surface area for up to 6 h.

2. Hydrocortisone or hydrocortisone 21-butyrate or hydrocortisone 21-hemisuccinate was applied dermally (0.01–1.0%w/w) in suspension with isopropylmyristate or dissolved in 1,2-propanediol. The ointments were stiffened with 5% polyethylene 1500 or 1.2% methylcellulose respectively.

3. Hydrocortisone was slowly absorbed and did not reach a steady-state absorption rate during the experimental period.

4. No metabolites of hydrocortisone were found during ear perfusion. In the supernatant of skin homogenate, however, cortisone, hydrocortisone-20α-ol and another, as yet unidentified metabolite, were observed.

5. Hydrocortisone 21-butyrate was completely hydrolysed during dermal absorption, showing steady-state concentrations of hydrocortisone in the effluent. Hydrocortisone 21-hemisuccinate did not reach steady-state concentrations in the effluent. About two-thirds was hydrolysed during absorption.

6. During arterial perfusion approximately 30% of hydrocortisone 21-butyrate was hydrolysed whereas 97% of hydrocortisone 21-hemisuccinate remained intact.

7. First-pass ester hydrolysis in skin may be complete for the poorly absorbed glucocorticoids leading to metabolites of less lipophilicity.     

Tetradecylmaltoside (TDM) enhances in vitro and in vivo intestinal absorption of enoxaparin,a low molecular weight heparin

Tetradecylmaltoside (TDM) was evaluated as a potential gastrointestinal absorption enhancer for low molecular weight heparin (LMWH), enoxaparin. The in vitro efficacy of TDM (0.0625, 0.125 and 0.25% w/v) in enhancing transport of ³H-enoxaparin or ¹⁴C-mannitol was investigated in human colonic epithelial cells (C2_BBel). Metabolic stability of the drug was determined in C2_BBel cell extracts. Transepithelial electrical resistance (TEER) was measured before and after exposure of the cells to TDM. Enoxaparin was further administered to anesthetized Sprague–Dawley rats in oral formulations in the absence or presence of increasing concentrations of TDM and drug absorption was monitored by measuring anti-factor Xa activity in rat blood. In vitro permeability study shows that apparent permeability (P_app) of ³H-enoxaparin across C2_BBe1 cells was increased by 8-fold in the presence of 0.0625% TDM compared to untreated cells. The movement of ¹⁴C-mannitol across the cell monolayer followed a similar pattern in the presence of increasing concentrations of TDM. No degradation or depolymerization of enoxaparin was observed when the drug was incubated in C2_BBel cell extract. TEER was reversible after 60 min exposure of the cells to 0.0625% (w/v) TDM. Oral formulations of enoxaparin containing TDM administered to anesthetized rats significantly and rapidly increased gastrointestinal absorption as compared to those animals which received enoxaparin plus saline (p<0.05). In the presence of 0.125% TDM in the formulation, enoxaparin oral bioavailability was increased by 2.5-fold compared to the saline control group. Overall, the data on the effect of TDM on the in vitro and in vivo intestinal permeation of enoxaparin suggest that TDM may represent a promising excipient for use in oral LMWH formulations.     

Inhaled histamine increases the rate of absorption of sodium cromoglycate from the lung.

Since many factors may alter lung epithelial permeability (LEP) to water soluble molecules, the effect of histamine on the absorption and clearance of inhaled sodium cromoglycate was examined in seven mildly asthmatic patients with hyperresponsive airways and eight normal subjects. The subjects underwent histamine challenge to determine the provocative concentration of histamine required to reduce the forced expiratory volume in one second (FEV1) by 20% (PC20) from baseline. On two further visits they inhaled either saline placebo or histamine and 5 min later inhaled an aerosol containing sodium cromoglycate. Measurements of FEV1 were made and blood samples taken for analysis of plasma sodium cromoglycate concentration at intervals for 3 h. In the asthmatic group histamine inhalation led to a 24 +/- 4% reduction in FEV1 but had no effect on the normal subjects. When compared with inhaled saline, histamine increased the initial pulmonary absorption of SCG without influencing the total amount of drug absorbed in both asthmatics and normals. These observations suggest that the pharmacokinetics of inhaled sodium cromoglycate may be altered significantly by inflammatory mediators present at the site of drug absorption from the airways.     

注射用呋布西林钠与生理盐水在不同温度下的配伍稳定性考察

目的考察不同温度下15min内注射用呋布西林钠与生理盐水的配伍稳定性。方法采用紫外分光光度法测定30℃～60℃水浴中注射用呋布西林钠与生理盐水配伍后的含量变化。结果15min内50℃,下注射用呋布西林钠与生理盐水配伍后含量、紫外吸收光谱、外观基本不变．高于50℃时注射用呋布西林钠与生理盐水配伍后含量、紫外吸收光谱均有显著变化。外观略有变化。结论注射用呋布西林钠与生理盐水在50℃下可以配伍使用。     

Absorption of protein via the intestinal wall. A quantitative model

Intact, biological active insulin and pancreatic RNase can be absorbed from the intestinal lumen into the blood circulation. The absorption is dependent on the addition of bile acid (sodium cholate) and proteinase inhibitor. The quantitative absorption of insulin and pancreatic RNase has been demonstrated in an in situ model. The amount of insulin absorbed after 30 min from the ileum to the mesenteric vein was 0.025% of the initial amount. Sodium cholate (10 mg/ml) and 3000 KIU/ml aprotinin enhanced this absorption by 30 times. The amount of pancreatic RNase which was absorbed from the ileum to the blood was 0.002% of the initial amount during 30 min. Sodium cholate (10 mg/ml) and 3000 KIU/ml aprotinin increased the absorption by a factor of 200. No damage occurred to the intestine during the experimental procedures. The sieving characteristics of the intestinal wall were not altered by the presence of sodium cholate and proteinase inhibitor in the intestinal lumen. These results suggest that sodium cholate and proteinase inhibitors can facilitate the absorption of intact, biologically active proteins across the intestinal wall.     

Plasma renin activity and renal sodium and water excretion following infusion of arachidonic acid in rats

Plasma renin activity (PRA) and urinary sodium and water excretion were measured following infusion of the prostaglandin (PG) precursor arachiodonic acid (C20 : 4) in normal hydrated rats (saline i.v.: 0.5 ml/hr/100 g body weight) and in rats with moderate volume expansion (saline i.v.: 1.5 ml/hr/100 g body weight). Nonhypotensive doses of C20 : 4 (40–70 μg/min/100 g b.w.) increased PRA in both normal and volume-expanded rats (p < 0.05, and p < 0.025, respectively). In volume-expanded rats, C20 : 4 was followed by reduced urine volume (p < 0.01) and sodium excretion (p < 0.001) in comparison to volume-expanded control rats, whereas in normal hydrated rats these parameters remained unchanged after C20 : 4. The present results indicate that the C20 : 4-stimulated PG-synthetase system can increase PRA independently of the extracellular fluid volume. Futhermore, these results suggest a complex interrelationship between PG-synthetase action, activation of the renal renin—angiotensin system and urinary water and sodium excretion.     

The metabolic effects of dopamine in man

Summary The metabolic effects of dopamine have been investigated by its infusion in normal man with and without simultaneous somatostatin administration. Dopamine was infused into overnight fasted men at 1.5 µg/kg/min (n=6) and 3.0 µg/kg/min (n=5) for 120 min. Plasma dopamine concentrations at 120 min were 78±9 nmol/l and 117±17 nmol/l respectively, associated with a marginal rise in plasma noradrenaline. Dopamine (1.5 µg/kg/min) induced an early and sustained rise in plasma glucagon (48±9 pg/ml versus 19±6 pg/ml in saline controls at 10 min, p<0.01)and a transient elevation in serum growth hormone which peaked to 17.7 (range 4.5–71.8)mU/l at 60 min (7.2 (range 0.6–37.7) mU/l with saline, p<0.05), but did not alter serum insulin, blood glucose or other metabolite levels. At 3.0 µg/kg/min, dopamine in addition provoked mild and transient elevations in blood glucose and serum insulin. Somatostatin (250 µg/h) suppressed circulating insulin, glucagon, and growth hormone levels and abolished the small hyperglycaemic effect seen with the higher dopamine dose. Somatostatin alone induced a progressive rise in circulating non-esterified fatty acid and 3-hydroxybutyrate levels reflecting insulin deficiency. This rise in NEFA and 3-hydroxybutyrate was increased by dopamine particularly at the higher dosage (plasma NEFA; somatostatin alone, 1.08±0.13 mmol/l; somatostatin plus dopamine 3 µg/kg/min, 1.44±0.17 mmol/l at 120 min, p<0.01: blood 3-hydroxybutyrate; somatostatin alone, 0.32±0.04 mmol/l; somatostatin plus dopamine 3 µg/kg/min, 0.56±0.12 mmol/l at 120 min, p<0.05). Thus: 1) dopamine at pharmacological dosage has minor effects when other endocrine mechanisms are intact, 2) it enhances lipolysis and ketogenesis during somatostatin-induced insulin deficiency, 3) the hyperglycaemic effect of the higher dopamine dose is probably mediated through stimulated glucagon secretion.     

Prenalterol,an oral beta-1 adrenoceptor agonist,in the treatment of chronic heart failure

Summary The haemodynamic effects of prenalterol, a new beta-1 agonist, were studied in 10 patients with chronic heart failure. Following intravenous prenalterol infusions of 1 mg, 2.5 mg and 5 mg at 15 min intervals, oral slow release prenalterol 20 mg, 30 mg and 50 mg was given at 2 h intervals and then 50–100 mg bid for one month. There were no significant changes in heart rate or blood pressure. Cardiac output increased significantly from control of 4.4±0.9 l/min to a maximum of 5.8±1.8 l/min (p<0.01) following the 5 mg prenalterol infusion and this increase was maintained following oral prenalterol on Days 1 and 2 and at 1 month. Significant increases in stroke volume and stroke work indices and reduction in systemic vascular resistance were also observed. Maximum increases in cardiac output and stroke work index following intravenous prenalterol correlated significantly with maximum increases observed following oral prenalterol on Day 2. Non-invasive evaluation showed no change in echocardiographic left ventricular end-diastolic dimension but a significant reduction in left ventricular end-systolic dimension on Day 30. PEP/LVET was significantly reduced from control of 0.56±0.15 to 0.47±0.12 (p<0.05) on Day 2 and 0.49±0.09 (p<0.05) at 1 month. Treadmill exercise duration was significantly improved for the group at 1 month and no adverse effects were noted. Oral slow release prenalterol is a potentially useful new drug for patients with chronic heart failure.     

Influence of intravenous acetylsalicylic acid and sodium salicylate on human renal function and lithium clearance

Summary The influence of intravenous acetylsalicylic acid (ASA; D,L-lysine-mono-acetylsalicylate), equimolar doses of sodium salicylate (SA) and placebo (P) on renal function has been studied in 6 healthy female volunteers, in 150 mmol sodium balance, and in lithium (Li) steady state with a plasma Li between 0.6 and 0.8 mmol/l. Following a bolus injection of 0.5 g ASA, 0.444 g SA or P (50 ml saline) given over 10 min and a subsequent continuous infusion of 1.5 g ASA, 1.332 SA or P (150 ml saline) over 170 min, urine was collected for 3 h as well as 6 plasma samples at 30-min intervals. Plasma ASA levels were between 13.8 and 22.1 µg/ml and for SA they were 20.8 to 82.6 µg/ml during ASA infusion, and between 22.5 and 108.9 µg/ml for SA during SA infusion. Neither ASA nor SA caused a significant change in urine volume, in the renal clearances of Na, K, free water, osmolality, creatinine, inulin and p-aminohippurate (PAH) or in plasma Li level. Renal Li clearance was slightly reduced by SA, from 37.8 to 29.4 ml/min (p<0.05). Since renal prostaglandin (PG) synthesis (urinary PGE₂ excretion) was 60.6% suppressed by ASA and was not affected by SA, the decrease in Li clearance cannot be related to inhibition of cyclooxygenase in the kidney.     

Predicting rapid analgesic onset of ibuprofen salts compared with ibuprofen acid: Tlag,Tlow, Tmed,and a novel parameter,TCmaxRef

Objective: This study evaluated the early absorption characteristics of ibuprofen salt formulations and standard ibuprofen acid (the reference).

Methods: In this open-label, crossover, single-center study (NCT02452450) in 32 healthy, fasted adults receiving single oral doses (400?mg ibuprofen) of ibuprofen lysine, ibuprofen liquid capsule, ibuprofen sodium, ibuprofen acid, and paracetamol, intensive blood sampling was conducted for up to 6?h. Time between dosing and the start of absorption (T_lag); a novel parameter, time at which the test formulations (ibuprofen salts) reached the observed maximum plasma concentration (C_max) of the reference (standard ibuprofen acid) (T_CmaxRef); and time to achieve therapeutic plasma concentration were measured.

Results: Ibuprofen was absorbed more rapidly from the salt formulations than the reference; T_lag was 3.3–6.4?min for salt formulations compared with 10.9?min for the reference, and 100% of subjects had a T_lag ≤ 5?min for ibuprofen lysine, compared with 61% for ibuprofen liquid capsule, 21% for ibuprofen sodium, and 7% for the reference. T_CmaxRef was 3.22–5.74-times shorter for salt formulations than for the reference (all p?p?Conclusions: This study shows that ibuprofen salts are absorbed faster than ibuprofen acid. T_lag and T_CmaxRef demonstrated early start and increased speed of absorption of salts compared with the reference, and may predict more rapid onset of analgesia.     

Sodium Nitrite Prevents both Reductions in Circulating Nitric Oxide and Hypertension in 7‐Day Lead‐Treated Rats

Hypotensive effects of oral sodium nitrite have been reported as alternative sources of nitric oxide (NO) formation in animals and human beings. Reductions in NO bioavailability were observed in lead‐induced hypertension. However, no previous study has examined whether a single daily dose of sodium nitrite prevents the reductions in the NO bioavailability in lead‐induced hypertension. Then, we expanded previous reports and evaluated the effects of sodium nitrite in 7‐day lead‐treated rats. Wistar rats were divided into four experimental groups: Pb+sodium nitrite group received intraperitoneally (i.p.) 1st dose 8 µg/100 g of lead acetate and a subsequent dose of 0.1 µg/100 g, and daily treatment with sodium nitrite (45 mg/kg/day) or water (Pb group) by gavage for 7 days; Sodium nitrite group received i.p. 1st dose 8 µg/100 g of sodium acetate and a subsequent dose of 0.1 µg/100 g, and daily treatment with sodium nitrite (45 mg/kg/day) or water (saline group) by gavage for 7 days. Similar and higher whole‐blood lead levels (11.5 ± 1.2 and 13.2 ± 0.7 µg/dL) were found in lead‐exposed rats treated with either water or sodium nitrite (Pb or Pb+sodium nitrite, respectively; both p < 0.05 versus control groups). We found lower NO markers such as plasma nitrite and nitrite + nitrate (NOx) levels (both p < 0.05 versus controls) in lead‐exposed rats compared with normotensive (sodium acetate)‐treated controls (Pb group versus saline group; p < 0.05). Lead induced increases in systolic blood pressure (from 130 ± 2 to 164 ± 6 mmHg in Pb group; p < 0.05); however, both lead‐induced decreases in NO markers and hypertension (Pb+sodium nitrite group versus Pb group; both p < 0.05) were prevented by a single daily dose of sodium nitrite. In conclusion, these findings are consistent with the idea that impaired NO bioavailability contributes to the maintenance of elevated blood pressure in lead‐induced hypertension. Additionally, our results show that sodium nitrite exerts antihypertensive effects in lead‐induced hypertension and provide evidence that sodium nitrite prevents the impairment of NO, thus, reaffirming the relevance of nitrite as alternative source of recycling back to NO.     

The effect of chlorpromazine on the function of colonic and ileal mucosa in the anaesthetized rat.

1 The effect of chlorpromazine (Cpz) on the net fluxes of water and sodium in the ileum and colon has been studied in the anaesthetized rat. 2 Under control conditions both the ileum and colon absorbed water and sodium. Cpz (100 mumol/kg, s.c.) had no significant effect on these basal rates of absorption. 3 Intestinal secretion was stimulated by a combination of intra-arterial prostaglandin E1 (PGE1; 10 nmol kg-1 min-1) and intraluminal theophylline (25 mM). A marked potentiation occurred between PGE1 and theophylline in the stimulation of colonic and ileal secretion. 4 In the ileum, a dose-related inhibition of the PGE 1/theophylline-induced changes in the net fluxes of water and sodium was produced by Cpz (0.1 to 100 mumol/kg, s.c.). Under these conditions the inhibition of the secretagogue-induced changes was significant using Cpz at 1 mumol/kg (s.c.) and a dose of Cpz of 100 mumol/kg (s.c.) returned the net fluxes of both water and sodium to basal levels. 5 In the colon, Cpz, at doses of 0.1 and 1 mumol/kg subcutaneously did not inhibit the PGE1/theophylline-induced changes in the net fluxes of water and sodium, and, in contrast with the ileum, significant changes were only obtained with Cpz at 10 mumol/kg. Increasing the dose of Cpz to 100 mumol/kg further inhibited the net flux of sodium, but not that of water in the colon, and in each case the secretagogue-induced changes were not returned to basal levels.     

A note on some changes in the physical properties of Escherichia coli after heat treatment

Suspensions of Escherichia coli in water at 50, 55, 60 and 100° showed an increase in extinction and nephelometer readings, the rate of increase depending on the temperature. This is considered to represent varying degrees of alteration in bacterial cytoplasmic protein. No such increases at any temperature occurred with cells held in 0.9% w/v sodium chloride. Lysozyme induced no lysis in cells which had been heated in water or in saline.     

Solute Absorption from the Airways of the Isolated Rat Lung. III. Absorption of Several Peptidase-Resistant,Synthetic Polypeptides: Poly-(2-Hydroxyethyl)-Aspartamides

A series of samples of the synthetic polypeptide poly-,-[N(2-hydroxyethyl)-DL-aspartamide] (PHEA), containing covalently bound fluorophore, ethylcarbonyl-6-aminofluorescein, and exhibiting different molecular weight distributions with weight average molecular weights ranging from approximately 4 to 43 kD, was prepared and characterized. Aqueous solutions of the polymers were administered to the airways of isolated perfused rat lung preparations, and transfer to the perfusate was measured. Polymers administered directly to the perfusate were not degraded during the experiment. Polymer transfer rates were dependent upon starting molecular weight distribution, larger molecules being absorbed more slowly. In the case of a polymer with a median molecular weight of 7.2 kD, the absorbed species appeared to be smaller molecules than those which were originally administered. This was not the case for a 3.98-kD polymer; absorbed material had a gel permeation chromatography elution volume equivalent to that of the administered material. Absorption for the 3.98-kD polymer was found to be dose dependent. Approximately 70% absorption of a 0.2-mg dose occurred in 100 min. Much larger polymers (up to 11.65 kD) were also absorbed at finite rates. Results are discussed in the context of macromolecular delivery to the systemic circulation via the lung.     

The Effects of Absorbed Water on the Properties of Amorphous Mixtures Containing Sucrose

Purpose. To measure the water vapor absorption behavior of sucrose-poly(vinyl pyrrolidone) (PVP) and sucrose-poly(vinyl pyrrolidone co-vinyl acetate) (PVP/VA) mixtures, prepared as amorphous solid solutions and as physical mixtures, and the effect of absorbed water on the amorphous properties, i.e., crystallization and glass transition temperature, T_g, of these systems. Methods. Mixtures of sucrose and polymer were prepared by co-lyophilization of aqueous sucrose-polymer solutions and by physically mixing amorphous sucrose and polymer. Absorption isotherms for the individual components and their mixtures were determined gravimetrically at 30°C as a function of relative humidity. Following the absorption experiments, mixtures were analyzed for evidence of crystallization using X-ray powder diffraction. For co-lyophilized mixtures showing no evidence of crystalline sucrose, T_g was determined as a function of water content using differential scanning calorimetry. Results. The absorption of water vapor was the same for co-lyophilized and physically mixed samples under the same conditions and equal to the weighted sums of the individual isotherms where no sucrose crystallization was observed. The crystallization of sucrose in the mixtures was reduced relative to sucrose alone only when sucrose was molecularly dispersed (co-lyophilized) with the polymers. In particular, when co-lyophilized with sucrose at a concentration of 50%, PVP was able to maintain sucrose in the amorphous state for up to three months, even when the T_g was reduced well below the storage temperature by the absorbed water. Conclusions. The water vapor absorption isotherms for co-lyophilized and physically mixed amorphous sucrose-PVP and sucrose-PVP/VA mixtures at 30°C are similar despite interactions between sugar and polymer which are formed when the components are molecularly dispersed with one another. In the presence of absorbed water the crystallization of sucrose was reduced only by the formation of a solid-solution, with PVP having a much more pronounced effect than PVP/VA. The effectiveness of PVP in preventing sucrose crystallization when significant levels of absorbed water are present was attributed to the molecular interactions between sucrose, PVP and water.     

Renal response of ethanol-treated dogs to increased filtered loads of sodium, bicarbonate, and chloride

Twenty, male, mongrel dogs were given either 3 g/kg (33% $\text{v}\text{v}$ solution) of ethanol or an isovolumetric quantity of water by oral intubation. Sixteen hours later the animals were anesthetized and after a control renal clearance, infused with either a hypertonic sodium chloride or sodium bicarbonate solution for an additional three clearance periods. The rate of infusion of solutions was increased progressively prior to each of the next periods. At each new rate, 45 min was permitted for equilibration before the clearance period. The hypertonic NaCl infusion produced similar increases in GFR, the filtered loads of Na and Cl, and the excretory rates of Na and Cl in both the water and ethanol groups. Although the hypertonic NaHCO₃ infusion produced equal increases in GFR and filtered loads of Na and HCO₃, there were dissimilar increases in Na and HCO₃ excretions. Sodium excretion increased by 17.1 ± 1.1 μeq/min/kg and percentage reabsorption decreased by 3.5 ± 0.3% in the water group while in the ethanol group, U_Na · V increased by 10.0 ± 1.4 μeq/min/kg (p < 0.01) and %R_Na decreased by 1.9 ± 0.2% (p < 0.01). In the ethanol group, bicarbonate excretion increased by 8.1 ± 1.3 μeq/min/kg and in the water group by 12.3 ± 1.1 μeq/min/kg (p < 0.05). The reduction in %R_HCO3 was significantly less in the ethanol group in comparison to the water group (8.1 ± 1.0 vs 12.1 ± 0.8%). Known effectors of sodium bicarbonate reabsorption, i.e., volume status, pCO₂, potassium stores, and filtration rate were not different between groups. It is concluded that ethanol pretreatment ameliorated the depressant effect of the NaHCO₃ infusion on tubular reabsorption.     

The influence of food intake on the effect of two controlled release formulations of furosemide

Differences in the urinary excretion rate of furosemide may explain discrepancies observed between the bioavailability and the total diuretic effect of different formulations of this drug. Furosemide was given at a dose of 60 mg as two oral controlled release (CR) formulations (FR and LR), with and without breakfast, in a randomized, four-treatment, four-period, crossover design to 28 healthy volunteers. Urinary volume, and contents of furosemide and sodium, were measured in samples taken over 24 h. The extent and rate of absorption of furosemide from FR were decreased after breakfast as compared to fasting: the mean (SD) of total furosemide excreted decreased from 11.38 (3.12) to 7.73 (1.67) mg, p<0.0001, and the median (range) mean residence time increased from 6.3 (4.1–9.3) to 9.5 (5.9–11.8) h, p <0.001. On the other hand, the extent of absorption of LR was increased after breakfast, from 8.04 (3.32) to 9.45 (1.83) mg, p <0.05, without a significant change in MRT. FR had a higher extent and rate of absorption than LR during fasting, but its extent of absorption was lower than that of LR in the postprandial state. Interestingly, the total fraction of furosemide absorbed, as estimated from total furosemide excretion, was not correlated with the total diuresis (r² = 0.079) and the differences in drug response compared among the four periods were much smaller than would be expected from the differences in amount absorbed. This discrepancy may be explained by differences in urinary excretion rate of furosemide and, related to this, differences in efficiency profiles between the four treatments. Therefore, the urinary excretion profile of a formulation of furosemide may be more important for the cumulated drug effect than the amount absorbed.     

Effects of Dose and Routes of Exposure on the Disposition of 2,3,7,8-[H]Tetrabromodibenzo-p-dioxin (TBDD) in the Rat

Polybrominated dibenzo-p-dioxins and dibenzofurans are of major concern because of potential occupational and environmental exposures and their structural similarity to the highly toxic chlorinated analogues. 2,3,7,8-Tetrabromodibenzo-p-dioxin (TBDD) is a closely related analogue in both structure and activity to the most toxic isomer 2,3,7,8-tetrachlorodibenzo-p-dioxin. The objectives of this study were to characterize the effects of dose and routes on absorption, excretion, and terminal tissue distribution of [³H]TBDD in the rat 72 hr after dosing. Rats were treated orally by gavage with 1, 10, 100, or 500 nmol/kg, intratracheally with 1 nmol/kg, or dermally with 1 nmol/kg (200 pmol/l.8 cm²). TBDD exhibited nonlinear oral absorption kinetics with maximum absorption (80%) occurring at dose ≤10 nmol/kg. similar to the transpulmonary absorption. In contrast, dermal absorption of TBDD was low (12%). The major tissue depots of radioactivity were liver, adipose tissue, and skin. Tissue distribution of the oral dose was dose-dependent, with disproportionally greater hepatic concentrations occurring at absorbed doses of >8 nmol/kg. Liver:adipose tissue (L:F) concentration ratios were 2.9 to 6.6 (lowest to highest oral dose, respectively). The lower L:F ratios obsened for the dermal and intratracheal doses at 1 nmol/kg (1.5 and 2, respectively) were likely due to differences in absorbed dose and dose-related tissue distribution. Elimination of radioactivity in feces, the major route of excretion for all dose groups and routes, and urine was also nonlinear with respect to the oral dose. The results of the present study provide important considerations for high- to low-dose and route-to-route extrapolations with TBDD and other dioxins and furans in human risk assessments.     

Tissue Distribution of [14C]Sucrose Octasulfate following Oral Administration to Rats

Purpose. Aluminum sucrose octasulfate (SOS) is used clinically to prevent ulcers. Under physiologic conditions, the sodium salt of this drug can be formed. Our objective was to determine whether sodium SOS was absorbed when administered orally. In addition to furthering our understanding of aluminum SOS, this study also aimed to clarify how other polyanionic drugs, such as heparin and low-molecular-weight heparins, are absorbed. Methods. [¹⁴C]-labeled and cold sodium SOS (60 mg/kg) were given to rats by stomach tube. Radioactivity was counted in gut tissue, gut washes, and nongut tissue (i.e., lung, liver, kidney, spleen, endothelial, and plasma samples) at 3 min, 6 min, 15 min, 30 min, 60 min, 4 h, and 24 h, and in urine and feces accumulated over 4 h and 24 h. Results. Peak radioactivity was found in the tissue and washes of the stomach, ileum, and colon at 6 min, 60 min, and 4 h, respectively, showing progression through the gut. Gut recovery accounted for 84% of the dose at 6 min but only 12% of the dose at 24 h, including counts from feces. Radioactivity was recovered from nongut tissue (averaging 8.6% of the dose) and accumulated urine (18% of the dose at 24 h). When total body distribution was considered, the recovery of radioactivity was greater for the endothelium than for plasma (peak percentage of the dose was 65% at 15 min, 20% at 3 min, 5% from 20 to 240 min for the vena cava, aortic endothelium, and plasma, respectively). Conclusions. Results indicate that sodium SOS is absorbed, agreeing with previous studies demonstrating the oral absorption of other sulfated polyanions. Endothelial concentrations must be considered when assessing the pharmacokinetics of these compounds. The measured plasma drug concentrations reflect the much greater amounts of drug residing with the endothelium.