Griseofulvin absorption from different sites in the human small intestine

The site-dependent small-intestinal absorption pattern of griseofulvin was investigated in man. Griseofulvin was chosen as a model substance having extremely low water solubility and moderate lipid solubility. A conventional steady-state perfusion technique (triple-lumen tubing system with a 20 cm test segment) was applied. Dissolved griseofulvin (10.0 mg L^?1) was perfused (10 mL min^?1) during 160 min into different parts of the small intestine with the middle of the test segment between 85 cm and 270 cm beyond the teeth. Each of the ten healthy volunteers was examined twice with the test segment localized in different regions to allow for intraindividual comparisons. Mean drug absorption rates calculated from intestinal aspirate concentrations were similar in the two intestinal parts (proximal, 15.0 ± 5.9 μg (20cm min)^?1; distal, 16.2 ± 4.3 μg (20 cm min)^?1; mean ± SD). Absorption rate was strongly correlated to the amount of griseofulvin offered to the test segment per unit time. Extrapolating these findings it follows that an amount of griseofulvin, once dissolved, would be absorbed completely (>99%) along 100 cm of the small intestine. A significant, positive correlation between the rate of transmucosal fluid transport and the absorption rate of griseofulvin was observed in the distal parts investigated.     

In vitro release and intestinal absorption of physostigmine salicylate from submicron emulsions

The in vitro release of physostigmine salicylate (PS) from a submicron emulsion and an aqueous solution was studied using the dialysis bag method. These formulations were then perfused to various locations along the rat small intestine (proximal, mid, and distal jejunum), and two lengths (10 and 55 cm). The disappearance of PS from the luminal compartment and its appearance in the blood compartment was monitored. In the in vitro drug release from emulsion experiments, a biphasic appearance of PS in the sink solution was observed, suggesting a possible sustained release from the emulsion. However, absorption data from perfusion studies did not correlate with this in vitro observation. No significant difference was found in absorption from emulsion versus solution in the mid jejunum where PS absorption was maximal. The difference between the two liquid formulations was observed only in those intestinal segments where the absorption was relatively low [absorption rate values of 4.6 +/- 0.86 and 9.98 +/- 2.04 (log%/min) x 10(-3) in the proximal and distal parts of the small intestine, respectively, as compared with 14.0 +/- 1.2-14.8 +/- 1.1 (log%/min) x 10(-3) in the mid jejunum]. In the distal part of the rat small intestine, PS was absorbed significantly better from solution than from the submicron emulsion. Cholinesterase activity in blood samples collected after intestinal perfusion with emulsion or solution revealed lower enzyme activity following emulsion administration.     

Intestinal transport of cefuroxime axetil in rats: absorption and hydrolysis processes

Studies were performed using three cefuroxime axetil solutions (11.8, 118 and 200 microM) in three selected intestinal segments and one cefuroxime axetil solution (118 microM) in colon of anaesthetized rats. First-order absorption rate pseudoconstants, k(ap) and effective permeability coefficients, P(eff), were calculated in each set. Absorption of cefuroxime axetil can apparently be described as a carrier-mediated transport, which obeys Michaelis-Menten and first order kinetics in the proximal segment of the small intestine and a passive diffusion mechanism in the mean and distal segments. The absorption kinetic parameters for cefuroxime axetil were obtained: Vm=0.613 (0.440) microM min-1; Km=31.49(28.31) microM and ka=0.011(0.003) min-1. Parameters characterizing degradation of the prodrug were obtained in each intestinal segment: proximal segment k(dp)=0.0049(0.0003) min-1, mean segment, k(dm)=0.0131(0.0007) min-1 and distal segment k(dd)=0.019(0.0009) min-1. Therefore, in situ intestinal absorption of cefuroxime axetil in the proximal segment of the rat in the presence of variable concentrations of cefadroxil has been investigated in order to examine the inhibitory effect of cefadroxil on cefuroxime axetil transport. The data suggest that cefadroxil and cefuroxime axetil share the same intestinal carrier.     

Evaluation of the skin uptake of mercuric chloride in man

Skin on the forearms of male human volunteers was exposed to aqueous HgCl2 solutions. It was assumed that loss of mercury from the test solution was equivalent to percutaneous absorption. Two parameters important for influencing uptake considered as the rate of absorption were investigated: the concentration of HgCl2 solutions (0.01, 0.1 and 0.2 M) and the time of exposure (5, 10, 15, 30 and 60 min). The absorption rate from 0.1 M HgCl2 solution decreased from 9.3 micrograms cm-2 min-1 during a 5 min exposure to 2.5 micrograms cm-2 min-1 during a 1 h exposure. A ten-fold decrease of HgCl2 concentration resulted in an approximately ten-fold decrease of the absorption rate, from 4.6 to 0.4 microgram cm-2 min-1 during a 30 min exposure. The results indicate that the absorption rate is a directly related function of concentration and an indirectly related function of time of exposure.     

环糊精包合作用对在体大鼠肠道P-糖蛋白药泵的影响

目的研究环糊精包合作用对P-糖蛋白底物药物体内吸收的影响。方法以P-糖蛋白底物盐酸小檗碱为模型药物,使用大鼠在体单向肠灌流装置,采用高效液相色谱法分别测定灌流液中盐酸小檗碱和酚红的浓度变化;研究2-羟丙基-β-环糊精(HP-β-CyD)对盐酸小檗碱肠道吸收的影响,以此评价环糊精包合作用对P-糖蛋白药泵的影响。结果盐酸小檗碱、盐酸小檗碱/HP-β-CyD物理混合物及盐酸小檗碱/HP-β-CyD包合物在大鼠空肠的吸收速率常数(Ka)分别为(0.45±0.029)、(0.70±0.087)、(2.39±0.119)×10-2·min-1,有效渗透系数(Peff)分别为(0.43±0.028)、(0.63±0.098)、(2.17±0.145)×10-3min·cm-1。HP-β-CyD对盐酸小檗碱的包合作用促进了大鼠肠道对盐酸小檗碱吸收。HP-β-CyD与盐酸小檗碱混合给药也能促进药物的吸收,但其作用远低于包合作用。结论环糊精的包合作用将有可能成为提高P-糖蛋白底物药物生物利用度的有效手段。     

Propranolol uptake with high capacity by rat perfused lung

Lung isolated from 7-week-old rats was perfused with pH 7.4 Krebs-Ringer bicarbonate buffer solution (35 mL) containing 1 to 100 micrograms mL-1 of propranolol and 3% BSA at the recirculation rate of 8 mL min-1. Almost parallel bi-exponential drug concentration-time curves were obtained at the initial load lower than 10 micrograms mL-1, whereas relatively slow, mono-exponential decline was found after perfusion at 100 micrograms mL-1. Pharmacokinetic analysis for the perfusate propranolol concentration-time curves when loaded at 1 to 10 micrograms mL-1 yielded almost comparable values for the pulmonary perfusion clearance (0.387 +/- 0.092 to 0.486 +/- 0.095 mL min-1 g-1). In contrast, this parameter was significantly reduced at 100 micrograms mL-1 (0.113 +/- 0.042 mL min-1 g-1). The present findings suggest a trend towards saturation kinetics in the in-vitro pulmonary clearance of propranolol.     

Jejunal and ileal absorption of oxprenolol in man: influence of nutrients and digestive secretions on jejunal absorption and systemic availability.

1 Study I evaluated the absorption of oxprenolol in the ileum, compared to jejunum, in healthy volunteers by an intestinal perfusion technique. Around 80 mg of drug were delivered as a saline solution directly in the small bowel. 2 Samples taken 30 cm distally to the site of perfusion showed that 63% of perfused oxprenolol was absorbed in the jejunum and 48% in the ileum; the differences were significant. 3 The plasma concentration-time profiles were similar for the two perfusions. The AUC and Cmax values of free and conjugated oxprenolol for the jejunal perfusion were significantly lower than those of ileum. They showed large but consistent intersubject variations in the two treatments. 4 Study II investigated, using the same technique, the influence of nutrients and digestive secretions on jejunal absorption and systemic availability of this drug. A saline (in treatments A and B) or a nutrient (in treatment C) solution containing oxprenolol was perfused into the jejunum below a balloon either inflated (A) or deflated (B and C). 5 The disappearance rate of oxprenolol from the jejunum was unaffected by endogenous secretions. The mean amount of drug absorbed along a 30-cm jejunal segment accounted for 52 (A) and 57% (B) of the total amount perfused. The intestinal absorption rate was markedly increased in the presence of nutrients (mean amount absorbed 96% for C). 6 The change in the rate of disappearance from the intestine had no effect on the systemic availability of oxprenolol (mean AUC values 8740, 8250 and 8020 nmol l-1 h for A, B and C, respectively) or its elimination from plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of pirenzepine on gastric emptying and salivary flow rate: constraints on the use of saliva paracetamol concentrations for the determination of paracetamol pharmacokinetics.

1. The effects of pirenzepine on gastric emptying, salivary flow and saliva paracetamol concentrations were investigated in healthy volunteers. 2. Pirenzepine significantly reduced the area under the saliva flow-time curves (7.29 +/- 3.30 g min-1 h without pirenzepine; 4.19 +/- 2.59 g min-1 h with pirenzepine, P less than 0.01). Pirenzepine had no significant effect on plasma paracetamol Cmax (17.5 +/- 7.8 micrograms ml-1 without pirenzepine; 12.6 +/- 7.7 micrograms ml-1 with pirenzepine), plasma tmax (0.2 h (0.2-0.8 h) without pirenzepine; (0.2 h 0.2-0.8 h) with pirenzepine) and plasma AUC(0.6 h) (32.3 +/- 7.2 micrograms ml-1 h without pirenzepine; 30.3 +/- 6.5 micrograms ml-1 h with pirenzepine). 3. Mean ratios of saliva:plasma paracetamol AUC (1.06 +/- 0.24 without pirenzepine; 1.84 +/- 0.48 with pirenzepine, P less than 0.001) and saliva:plasma paracetamol Cmax (1.7 +/- 1.0 without pirenzepine; 6.5 +/- 2.7 with pirenzepine, P less than 0.01) were significantly increased by pirenzepine pretreatment, but there was a poor correlation between the percentage change in the area under the saliva flow-time curve and the percentage change in saliva paracetamol AUC (r = 0.47, P = 0.21). 4. The findings suggest that a) pirenzepine is a more selective antagonist of the muscarinic receptors in salivary glands than those in gastric smooth muscle and b) caution is required when using saliva paracetamol concentrations to determine the pharmacokinetics of the drug in the presence of other agents which may influence salivary flow rate.     

Age-dependent propranolol clearance in perfused rat liver

The effect of age on the hepatic clearance of propranolol was studied by perfusing the liver isolated from 3- to 104-week-old rats. Propranolol levels in the recirculating perfusate declined biexponentially with time in all age groups. When the liver isolated from 7-week-old rats was perfused with propranolol (1 microgram/ml, 100 ml), hepatic clearance of this drug by the perfused liver (CLperf) increased from 0.589 to 1.14 ml X min-1 X (g liver)-1 with the increase of the perfusion flow rate from 1.0 to 2.0 ml X min-1 X (g liver)-1, confirming evidence of "perfusion-limited" hepatic clearance for this drug. Furthermore, there was no initial concentration(dose)-dependence in CLperf up to 2.5 micrograms/ml (i.e. 250 micrograms/organ). The effect of age on CLperf was then investigated by perfusing the isolated liver with 1.0 micrograms/ml propranolol at 2.0 ml X min-1 X (g liver)-1. Elimination of this drug from the perfusion medium was relatively rapid in 5- to 7-week-old rats, yielding the highest CLperf in these relatively young rats [approximately 1.0 to 1.1 ml X min-1 X (g liver)-1]. In contrast, CLperf values in both immature and older rats were 0.5 ml X min-1 X (g liver)-1 or less. The in vitro intrinsic hepatic clearance estimated in 5- and 7-week-old rats was about ten times as high as that in 104-week-old rats.     

The gastrointestinal absorption of paracetamol in the rat.

The absorption of [3H]paracetamol by rat small intestine, colon and stomach was studied in vivo and in vitro. Small intestinal in vivo studies, using a wide range of drug concentrations, showed that absorption was efficient and uniform throughout the small bowel, no site showing preferential absorption. Double reciprocal and direct plots indicated first order kinetics. The pattern was not observed when uptake was occurring from high concentrations of paracetamol in suspension. Gastric and colonic in vivo studies showed that there was appreciable absorption of [3H]paracetamol from these sites. In vitro studies using everted intestinal sacs showed no effect on paracetamol transfer when the incubation temperature was lowered to 10 degrees C or when iodoacetate (5 X 10(-2)M) and 2.4 dinitrophenol (5 X 10(-4)M) was added to the incubation medium. There was, however, a significant reduction in transfer of paracetamol against a concentration gradient of 10:1 applied across the mucosa. These data suggest that the uptake of paracetamol is by a passive transport process and confirm the efficiency of paracetamol absorption observed indirectly by others.     

Serum drug concentrations after oral administration of paracetamol to patients with surgical resection of the gastrointestinal tract.

Serum concentrations of paracetamol were measured at 30, 60, 120 and 180 min after oral administration of a solution of 1500 mg paracetamol in normal subjects (n = 32) (Group A) and in patients with total gastrectomy (Roux-en-Y reconstruction) (n = 5) (Group B), distal partial gastrectomy (Billroth I reconstruction) (n = 7) (Group C), pylorus preserving pancreatoduodenectomy (Billroth I type reconstruction) (n = 12) (Group D), and short bowel syndrome (n = 5) (Group E). In Group B, the dose was delivery directly into the jejunum 20 cm distal to the duodenojejunal flexure. The highest serum drug concentrations were observed in the 30 min sample in Groups B and C and in the 120 min sample in Groups A, D, and E. Mean (+/- s.d.) concentrations at these times were 18.90 +/- 1.55 micrograms ml-1 (Group B), 12.89 +/- 2.12 micrograms ml-1 (Group C), 11.12 +/- 3.16 micrograms ml-1 (Group A), 9.78 +/- 2.85 micrograms ml-1 (Group D), and 4.89 +/- 1.96 micrograms ml-1 (Group E), respectively. We conclude that in patients with normal intact gastrointestinal tract, most of a dose of oral paracetamol is absorbed from the jejunum distal to the duodenojejunal flexure.     

Etretinate absorption in the in situ perfused intestinal lumen: preliminary studies in the rat

The absorption characteristics of etretinate were examined in the Sprague-Dawley rat with the use of the in situ intestinal lumen perfusion model. Intestinal segments of 15-50 cm were cannulated and perfused with etretinate solutions of 178-1405 micrograms ml-1 in a single-pass manner at flow rates of 0.15-0.96 ml min-1. The intestinal effluent was collected and analyzed by HPLC for etretinate, as was blood that was drawn from the jugular vein. Despite its lipophilic nature, etretinate does not appear to be well absorbed from the rat intestine; the maximum fraction disappearing from the intestinal lumen was approximately 0.35. The absorption of etretinate appeared to be controlled by the aqueous diffusion layer. There was no evidence that the uptake of etretinate by the gastrointestinal membrane involved an active transport system.     

Influence of bile salts and lipids on intestinal absorption of griseofulvin in man

Summary The influence of bile salts and lipids on the intestinal absorption of griseofulvin has been studied in 11 healthy male volunteers by the intestinal perfusion technique. The drug in a nutrient solution (Realmentyl) was perfused into the second part of duodenum at 5 ml/min. Intestinal samples were taken continuously at 1 ml/min, 20 cm (at the angle of Treitz) and 45 cm distal to the perfusion point. To study the effect of lipids on griseofulvin absorption, the drug was perfused with solutions A and B, of which B contained a total lipid and caloric load three times that of A. The influence of bile salts on griseofulvin absorption was examined by perfusing the drug on Day 1 with bile salts and again on the following day after bile salt depletion. Bile salts and a varying quantity of lipid perfusate had no significant influence on the duodeno-jejunal griseofulvin absorption rate per cm of intestine. Lipids, however, may still play a role in griseofulvin absorption along the entire intestine.     

水飞蓟宾在大鼠小肠中的吸收特性

目的考察水飞蓟宾在大鼠各肠段的吸收。方法以一定浓度的水飞蓟宾溶液作为灌流液，以0.1 mL·min^-1进行大鼠不同肠段的单向灌流,于不同时间收集肠灌流液并肝门静脉取血，分别用HPLC测定灌流液和血中药物浓度。结果实验结果表明190 μg·mL^-1水飞蓟宾在不同肠段的吸收速率常数(k_a)和有效透过系数(P_eff)是十二指肠>空肠>回肠>结肠。质量浓度为80 μg·mL^-1的水飞蓟宾灌流液在十二指肠的吸收与190和300 μg·mL^-1的吸收情况均有显著性差异(P<0.05)，但质量浓度为190 μg·mL^-1与300 μg·mL^-1的吸收之间无显著性差异(P>0.05)。肝门静脉血中药物分析也显示十二指肠>空肠>回肠>结肠。结论水飞蓟宾在小肠全肠道均有吸收且有高浓度饱和现象。     

Paracetamol metabolism in the isolated perfused rat liver with further metabolism of a biliary paracetamol conjugate by the small intestine

The isolated, perfused rat liver metabolized paracetamol to glucuronide. sulphate and glutathione conjugates. Sulphate conjugation was the preferred route of metaholism at the drug concentrations studied, but formation of glutathione conjugate became increasingly prominent at higher paracetamol concentrations. Sulphate conjugation was saturated at a paracetamol concentration in the perfusatc of 5 mM. while formation of glucuronide or glutathione conjugates was not yet saturated at 10 mM. The sulphate conjugate was predominantly excreted into the perfusate whereas the excretion pattern for the glucuronide and glutathione conjugates changed with time. Initially, both these conjugates were almost exclusively excreted in the bile, after 90 min perfusion mainly into the perfusate. Preformed paracetamol conjugates were not transferred from perfusate to bile by the isolated perfused liver. Freshly isolated intestinal cells rapidly converted paracetamol-S-glutathione to paracetamol-S-cysteine which was slowly acetylated to the,N-acetylcysteine derivative. Methionine stimulated, and serine-borate inhibited, the breakdown of paracetamol-S-glutathione by intestinal cells, indicating the involvement of γ-glutamyltranspeptidase in the reaction. Biliary paracctamol-S-glutathione was metabolized similarly by the small intestine in situ; the subsequent appearance of the cysteine conjugate in plasma revealed that breakdown of the glutathione conjugate occurred before or during passage through the intestinal wall. Direct absorption of paracetamol-S-cysteine from the intestinal lumen to the portal blood was verified by instillation of this derivative in the intestinal lumen in situ. Analysis of plasma also indicated enterohepatic circulation and reabsorption of biliary paracetamol and paracetamol glucuronide from the intestinal lumen.     

在体猪耳静脉灌流经皮吸收模型的建立与应用

目的建立在体猪耳静脉灌流经皮吸收模型，为经皮吸收制剂研究提供新方法。方法建立在体猪耳静脉灌流经皮吸收模型。以葡萄糖利用试验及乳酸脱氢酶活性检测评价模型的生物学活性，以酮洛芬异丙酯和水杨酸甲酯为模型药物考察系统的应用。结果葡萄糖利用及乳酸脱氢酶活性检测表明系统7 h内保持良好生物学活性。酮洛芬异丙酯经皮渗透过程中被完全代谢为酮洛芬，稳态时酮洛芬累积形成量Q与时间t回归的方程为Q=-0.024+0.120t，形成速率为0.120　μg·cm^-2·h^-1。水杨酸甲酯经皮渗透过程中部分被代谢为水杨酸，稳态时水杨酸甲酯累积渗透量Q与时间t回归的方程为Q=-3.809+6.129　t，渗透速率为6.129　μg·cm^-2·h^-1；水杨酸累积形成量Q与时间t回归的方程为Q=-1.785+0.879　t，形成速率为0.879　μg·cm^-2·h^-1。结论该模型操作简便、价格经济，不仅可以考察药物的经皮吸收，而且能够用于研究药物的皮肤代谢。     

In situ studies of regional absorption of lobucavir and ganciclovir from rabbit intestine and predictions of dose-limited absorption and associated variability in humans

The regional absorption of lobucavir (LBV), an experimental antiviral agent, and ganciclovir (DHPG) was investigated in rabbit intestine using an in situ single-pass perfusion technique. Duodenal, jejunal, and colonic segments in anesthetized rabbits were perfused with drug solutions in a hypotonic buffer at 0.2 mL/min. Effluent perfusate samples for drug analysis were collected every 10 min for 180 min. To account for water absorption during perfusion, an intestinal absorption model was developed to estimate the absorptive clearance (PeA): PeA=Qavexln((QinxCin)/(QoutxCout)), where Qave is a logarithmic average of the inflow (Qin) and outflow perfusion rate (Qout); Cin and C(out) are drug inflow and outflow concentrations. The PeA of LBV in the duodenum and jejunum was 2.1+/-0.77 and 1.7+/-0.46 microL/min/cm (n=3), respectively, 4.8- and 3.0-fold higher than that of DHPG in the same animals. However, LBV PeA decreased significantly in the colon (0.47+/-0.11 microL/min/cm) and was similar to that of DHPG which exhibited no regional differences in absorption. The interplay between PeA and solubility was studied using a compartmental absorption and transit model, and simulations were performed to investigate dose-limited absorption and the sources of variability in absorption where two compounds differ significantly. The dose range where absorption started to decrease was predicted using the model, with LBV exhibiting the phenomenon at a lower dose than DHPG (450 vs. 750 mg). Furthermore, the intersubject variability in human absorption of both compounds was reproduced when the variability in both PeA and the small intestinal transit time was considered in the model. The variability in the ascending colonic transit time also contributed to the intersubject variability observed for DHPG. The results demonstrate value of integrating in situ studies and modeling in predicting these absorption characteristics.     

The gastrointestinal absorption of paracetamol in the rat

The absorption of [³H]paracetamol by rat small intestine, colon and stomach was studied in vivo and in vitro. Small intestinal in vivo studies, using a wide range of drug concentrations, showed that absorption was efficient and uniform throughout the small bowel, no site showing preferential absorption. Double reciprocal and direct plots indicated first order kinetics. The pattern was not observed when uptake was occurring from high concentrations of paracetamol in suspension. Gastric and colonic in vivo studies showed that there was appreciable absorption of [³H]paracetamol from these sites. In vitro studies using everted intestinal sacs showed no effect on paracetamol transfer when the incubation temperature was lowered to 10 °C or when iodoacetate (5 times 10^?2m) and 2.4 dinitrophenol (5 times 10^?4m) was added to the incubation medium. There was, however, a significant reduction in transfer of paracetamol against a concentration gradient of 10:1 applied across the mucosa. These data suggest that the uptake of paracetamol is by a passive transport process and confirm the efficiency of paracetamol absorption observed indirectly by others.     

利巴韦林大鼠肠吸收动力学

目的研究利巴韦林在大鼠各肠段的吸收动力学特征。方法应用大鼠在体灌流肠吸收实验考察其吸收动力学 ;采用HPLC法测定利巴韦林在大鼠体内肠吸收回流液中的药物浓度 ;采用UV法测定回流液中酚红浓度的变化。结果利巴韦林在小肠中上部吸收较好 ,吸收速率按十二指肠、空肠、回肠、结肠依次下降 ,吸收速率常数依次为 0 0 970 0、0 0 15 0 0、0 0 0 110、0 0 0 0 0 5h-1;回流液中吸收药物的量与利巴韦林的浓度成正比。结论利巴韦林在肠道的吸收呈一级吸收动力学特征 ,吸收机制为被动吸收 ;主要吸收部位为十二指肠和小肠上部 ,结肠几乎无吸收 ;提示该药适合制成日服 2次的缓释制剂     

Intestinal absorption of fluoride at high luminal concentration of fluoride

The paper reports that high fluoride concentrations in the intestinal lumen hinders the absorption of this anion. This conclusion was verified with three different experimental models. Pharmacokinetic experiments done in human volunteers revealed that the bioavailability of fluoride from sodium fluoride (NaF, CAS 7681-49-4) enteric coated tablets was 33% of that of plain (immediate release) tablets. The latter findings were confirmed in rats receiving 1 ml of NaF solutions (40, 80 or 160 mmol/l) by gavage. The greatest AUC (area under the curve of fluoremia as a function of time) was obtained with an oral dose of 80 mumol of NaF. This parameter was significantly greater (p < 0.01) with 80 mumol than with 40 mumol NaF, but similar to that observed with 160 mumol. Fecal fluoride excretions (in the 24 h following a single dose of NaF) and the bone fluoride contents (found at the end of 30 days of treatment with 40, 80 or 160 mumol NaF/day), agreed with the AUC values. The rate of fluoride absorption (v, mumol/10 min) through the intestinal wall was investigated with perfused, isolated rat duodenum in vivo. Fluoride absorption increased between 0 and 10 mmol/l luminal fluoride and decreased with higher concentrations. Oxygen consumption of duodenal-tissue decreased exponentially between zero (1.12 mumol O2 min-1 g-1) and 10 mmol/l fluoride (0.45 mumol O2 min-1 g-1).