Absorption and metabolism of capsaicinoids following intragastric administration in rats

Summary This study was performed to examine the metabolism and absorption of intragastrically administered capsaicinoids in the anaesthetized rat.[³H]-dihydrocapsaicin ([³H]-DHC) and unlabelled capsaicin were readily absorbed from the gastrointestinal tract but were almost completely metabolized before reaching the general circulation. A certain degree of biotransformation already took place in the intestinal lumen. Unchanged compounds (identified by chromatography) were present in portal vein blood. There seems to be a saturable absorption and degradation process in the gastrointestinal tract and a very effective metabolism in the liver.Less than 5% of the total amount of extracted radioactivity consisted of unchanged [³H]-DHC in trunk blood and brain 15 min after gastrointestinal application. On the other hand, approximately 50% unchanged [³H]-DHC was detected in these tissues 3 min after i.v. or 90 min after s.c. application of the capsaicinoids. Dihydrocapsaicin (DHC) or [³H]-DHC were metabolized when incubated in vitro with liver tissue but not with brain tissue. The metabolic product(s) did not show capsaicin-like biological activity.It can be concluded that rapid hepatic metabolization limits systemic pharmacological effects of enterally absorbed capsaicin. Send offprint requests to J. Donnerer at the above address     

Intestinal absorption and excretion of aflatoxin in rats

Aflatoxin B1 (AFB1) transfer across the gastrointestinal tract was studied in rats. The rate of biliary secretion of 3H was higher when [3H]AFB1 was injected into the small intestine than when injected into the stomach. When various sites of the small intestine were perfused with the medium containing [3H]AFB1, the highest rate of disappearance of 3H from the medium was noted in the duodenum. Also the rate of biliary secretion of 3H tended to be higher when the duodenum was perfused than when the other sites were perfused. These results suggest that AFB1 is absorbed mainly from the small intestine, most efficiently from the duodenum. Uptake of AFB1 by the everted intestine in vitro was slightly greater in the jejunum than the other sites, suggesting that the cause of the differences in the intestinal absorption among various sites may reside in the transfer process of AFB1 from the epithelial cell layer to vascular circulation. Comparison of the AFB1 appearance in the mesenteric venous plasma and lymph showed that AFB1 is absorbed almost exclusively in the vein. Distribution of 3H in the mesenteric plasma on thin-layer chromatography revealed that metabolic degradation of AFB1 takes place in the duodenal and jejunal tissues during the course of AFB1 absorption. Examination of the appearance of AFB1 or 3H in the intestinal perfusate after iv injection of of AFB1 or [3H]AFB1 suggested that AFB1 and its metabolites can transfer from the blood to the intestinal lumen. The rate of the AFB1 absorption from various sites of the intestine changed with age and reproductive stage, indicating that the AFB1 transfer across the intestinal wall is under the influence of the growth and reproductive endocrine condition.     

Sumatriptan Absorption from Different Regions of the Human Gastrointestinal Tract

Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.     

The effect of site of administration in the gastrointestinal tract on the absorption of insulin from nanocapsules in diabetic rats.

Isobutylcyanoacrylate nanocapsules have been used as drug carriers for the enteral absorption of insulin. Their absorption has been studied by measuring fasted glycaemia in streptozotocin-induced diabetic rats after a single administration of encapsulated insulin (100 units kg-1) at various sites along the gastrointestinal tract. Glycaemia decreased from the second day, the intensity and duration depending on the site of administration (65% ileum, 59% stomach, 52% duodenum and jejunum, 34% colon). This hypoglycaemic effect lasted up to the 18th day after administration for ileum and jejunum, the 15th day for stomach and duodenum, and the 13th day for colon. In-vitro, nanocapsules protect insulin against proteolysis from pepsin, chymotrypsin and trypsin. These results suggest (i) that insulin is protected by nanocapsules in the gastrointestinal tract, (ii) that it is absorbed in an active form, and (iii) that ileum is the most potent site of absorption.     

Metabolic fate of the new angiotensin-converting enzyme inhibitor imidapril in animals. 1st communication: absorption, pharmacokinetics and excretion in rats and dogs.

Imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3- phenylpropyl]amino]propionyl]-1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) is an ester prodrug of the angiotensin-converting enzyme (ACE) inhibitor, 6366 A (CAS 89371-44-8). Absorption, pharmacokinetics and excretion of imidapril were studied in rats and dogs after oral and intravenous administration of [N-methyl-14C]-imidapril and [N-methyl-14C]-6366 A (1 mg/kg). Following oral administration of 14C-labeled imidapril and 6366 A to rats, plasma concentrations of radioactivity were much higher after [N-methyl-14C]-imidapril dosing than after [N-methyl-14C]-6366 A dosing at all time points. Imidapril was relatively rapidly absorbed from the digestive tract and easily metabolized to the pharmacologically active 6366 A after oral dosing in the rats and dogs. Thus, imidapril proved to be an orally usable 6366 A prodrug. More than 62% and 38% of the dose were assumed to be absorbed from the gastrointestinal tract in the rats and dogs, respectively. The in situ absorption study showed that [N-methyl-14C]-imidapril was absorbed from nearly the entire rat small intestine, especially from the jejunum, but hardly absorbed from the stomach. After oral administration, peak levels of radioactivity in the plasma occurred at 1 h in rats and 30 min to 2 h in dogs. The disappearance of unchanged drug from the plasma was much faster in rats than in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of 5-hydroxytryptamine on protein synthesis in gastrointestinal and other tissues and on serum gastrin concentrations in rats.

1 The effect of 5-hydroxytryptamine (5-HT) on protein synthesis in the gastrointestinal tissues as well as in the liver, heart and brain was studied by measuring [3H]-leucine incorporation into total tissue protein in vivo in rats. 2 A single injection of 5-HT (10 mg/kg) produced a marked inhibition (45 to 65%) in protein synthesis in the stomach (oxyntic gland area), intestine (jejunum + ileum), colon and brain, but not in the liver and heart. 3 Dose- and time-dependent studies of 5-HT-induced changes in protein synthesis in the stomach of fed rats revealed that the maximal inhibition of about 65% occurred 1 h after a dose of 12.5 mg/kg. 4 Animals deprived of food for 24 h differed from their fed counterparts only in the degree of responsiveness, in that a greater inhibition (75%) of [3H]-leucine incorporation into total protein of the stomach was observed 30 min after 5-HT injection. 5 Pretreatment of animals with methysergide (0.25 mg/kg) essentially abolished the 5-HT-mediated inhibition of protein synthesis in the stomach. 6 Serum gastrin concentration in fasted animals remained slightly elevated during the initial period of 5-HT treatment (up to 1 h). 7 The results demonstrate that in certain tissues, 5-HT markedly inhibits protein synthesis. The inhibition in protein synthesis in the gastrointestinal tract cannot be attributed to changes in the concentration of gastrin.     

豆腐果素缓释微丸的研究.Ⅱ.在大鼠胃肠道的吸收

采用在体灌流法考察了豆腐果素在大鼠胃肠道的吸收情况。根据该结果研制可持续释药12h的缓释微丸。试验结果表明，豆腐果素在大鼠胃、小肠各段均有吸收，在结肠处无吸收。豆腐果素缓释微丸与普通片剂相比，缓释微丸在狗体内的平均滞留时间（MRT）明显延长。     

~3H-米酵菌酸在大鼠体内的吸收、分布与排泄

用氚标记物研究了米酵菌酸在大鼠体内的吸收、分布与排出。结果表明,~3H-米酵菌酸经大鼠胃肠道吸收很快,灌胃后15min血浆及主要组织的放射比活性已达高峰,以肝脏为最高。24h内从尿粪排泄的放射性总量为灌胃剂量的70％。胆汁也是一条重要排泄途径,24小时内放射性总排泄量为34％。代谢物从胆汁排泄进入肠道后重新吸入肝,形成肠肝循环,使肝脏反复受到损害。     

Studies on the interaction between ethanol and serotonin metabolism in rat, using deuterated ethanol and 4-methylpyrazole

The metabolic interaction between ethanol and serotonin (5-hydroxytryptamine) via alcohol dehydrogenase (ADH; EC 1.1.1.1) was studied in tissue homogenates of Sprague-Dawley rats by following the transfer of deuterium from deuterated ethanol over endogenous NADH to 5-hydroxytryptophol (5HTOL). Homogenates of whole brain, lung, spleen, kidney, liver, stomach, jejunum, ileum, colon, and caecum were incubated in the presence of [2H2]ethanol and 5-hydroxyindole-3-acetaldehyde (5HIAL), and the [2H]5HTOL formed was identified and quantified using gas chromatography-mass spectrometry. ADH activity was most abundant in liver, kidney, and within the gastrointestinal tract. The highest incorporation of deuterium was obtained in homogenates of kidney, lung, and colon, whereas in brain, which contains very low ADH activity, no incorporation could be demonstrated. Addition of extra NAD+ (2.4 mM) increased the formation of [2H]5HTOL 2.6-fold in liver homogenates, but only 1.2-fold in kidney homogenates. 4-Methylpyrazole, a potent inhibitor of class I ADH, inhibited the 5HIAL reduction in homogenates of lung, kidney, jejunum, ileum, and colon, and caused a marked drop in 5HTOL oxidation in all tissues except stomach and spleen. These results demonstrate that in the rat a metabolic interaction between ethanol and serotonin via the ADH pathway may take place in several tissues besides the liver, which is the main tissue for ethanol detoxification.     

Metabolic fate of the new anti-ulcer drug enprostil in animals. 1st communication: absorption, distribution and excretion in the mouse, rat and rabbit

Absorption, distribution and excretion of [3H]-enprostil ((+-)-11a,15a-dihydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorpr osta -4,5,13(t)-trienoic acid methyl ester, TA-84135), a new anti-ulcer prostaglandin, were studied in mice, rats and rabbits. Radioactivity associated with enprostil was rapidly absorbed from the gastrointestinal tract with Tmax values of 15 or 30 min. Absorption was also efficient inasmuch as approximately 80% of an oral dose was recovered in bile and urine in 24 h in bile duct-cannulated rats. Experiments in pylorus-ligated, bile duct-cannulated rats demonstrated that enprostil was mainly absorbed from the intestine, rather than from the stomach. In mice given oral doses of 2, 8 and 32 micrograms/kg, Cmax and AUC values of enprostil radioequivalents increased proportionately to the increase in dose, indicating linear kinetics over this dose range. Distribution of enprostil-associated radioactivity was investigated in rats by quantitating tritium in various tissues after the oral administration of [3H]-enprostil. Radioactivity in tissues was highest at 15 or 30 min after dosing. Highest levels of radioactivity were found in the stomach and intestines, the organs which came into direct contact with the dose, and the liver and kidney, the organs involved in excretion of enprostil. The rate of elimination of enprostil-associated radioactivity from all tissues and from plasma was similar. Enprostil-associated radioactivity did not accumulate in any tissue. Radioactivity was found in fetuses following oral administration of [3H]-enprostil to rats on the 12th or 19th day of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intestinal absorption and secretion of ochratoxin A in the rat

The absorption and secretion of ochratoxin A (OA) by the gastrointestinal tract were studied in the rat. When OA was introduced into the lumen at various sites of the gastrointestinal tract, the largest concentration of OA in portal blood was found after the toxin was injected into the lumen at the proximal jejunum. After the injection of OA into a closed loop at the proximal jejunum, the rate of appearance of OA in the mesenteric venous plasma was higher than that in lymph. The rate of appearance in the venous plasma increased with an increase in the luminal concentration of OA while in the lymph the rate remained almost constant with respect to the luminal OA concentration. These results suggest that the site of maximal absorption is the proximal jejunum and that the primary route of absorption is the portal vein although the contribution of the lymphatic route cannot be excluded when low-dose levels of OA are given. When various parts of the gastrointestinal tract were perfused after iv injection of OA, noticeable amounts of the toxin appeared in the intestinal perfusate, suggesting that intestinal secretion may be another route of excretion of OA. Comparison of intestinal secretion and absorption showed asymmetric transfer of OA across the intestinal mucosa, the lumen-to-blood transfer being greater than that in the opposite direction.     

阿昔洛韦在大鼠胃肠道吸收的研究

目的：了解阿昔洛韦在大鼠胃肠道的吸收情况。方法：采用大鼠在体灌流技术，对阿昔洛韦在大鼠胃部及不同肠段的吸收进行了研究。结果：3h后胃中吸收平均值为9．46％，在小肠上部、中部、下部和结肠段的吸收百分率分别为20．22％，15．70％，9．15％和4．59％。结论：阿昔洛韦主要在胃肠道上部吸收，但吸收亦较差。     

全胃切除术后两种消化道重建术的效果比较

目的 比较改良袢式空肠代胃术与P型空肠代胃术的优缺点及临床应用价值.方法 56例胃癌患者依据胃切除术后消化道重建方式分为两组,观察组35例采取改良袢式空肠代胃术；对照组21例采取P型空肠代胃术,比较两组临床效果.结果 两组手术时间和术中出血量差异无统计学意义(P＞0.05).观察组排空时间[(61±23)min]较对照组[(37±19)min]长(t=3.03,P＜0.05),每次饮食量[(308±44) ml]较对照组[(262±34) ml]高(t=2.55,P＜0.05),每天饮食次数[(4.2±1.2)次]较对照组[(5.7±2.3)次]少(t=2.46,P＜0.05).观察组术后并发症发生率(14.3％)显著低于对照组(42.9％)(x2=5.71,P＜0.05).结论 全胃切除术后,采用改良袢式空肠代胃术重建消化道,相对于P型空肠代胃术,能有效提高患者术后生活质量,降低并发症发生率,但并未使手术过程复杂化.     

Ciprofloxacin absorption in different regions of the human gastrointestinal tract. Investigations with the hf-capsule.

1. The absorption of ciprofloxacin from different regions of the human gastrointestinal tract was investigated in four healthy males using a remote-controlled drug delivery device (hf-capsule). 2. Significant differences in AUC were observed in the control study (oral administration of ciprofloxacin solution without the hf-capsule = 100%) and after release of ciprofloxacin in the jejunum (geometric mean: 37%), the ileum (mean: 23%), the ascending colon (mean: 7%) and the descending colon (mean: 5%), whereas tmax showed no difference for any of the absorption sites. Ciprofloxacin release in the stomach resulted in the greatest AUC (mean: 140%). Thus, it is concluded that the main absorption site of ciprofloxacin is the upper gastrointestinal tract, up to the jejunum. 3. Differences in presystemic metabolism of known drug metabolites along the gut could be excluded, as the pattern of urinary recovery of desethylene-, sulpho-, and oxo-ciprofloxacin and the parent compound was similar for all drug release sites.     

HPLC法测定辣椒总碱中辣椒碱及二氢辣椒碱的含量

在 C6H5键合硅胶为填充剂的色谱柱上 ,以乙腈 - 0 .1% H3 PO4(33∶ 6 7)为流动相 ,检测波长为 2 80 nm,同时测定了辣椒总碱中辣椒碱及二氢辣椒碱的含量。结果表明 ,辣椒总碱中辣椒碱及二氢辣椒碱的含量约为5 8%和 30 % ,方法的平均加样回收率分别为 98.2 %和 97.6 %。     

Absorption of valproic acid from the gastrointestinal tract of the piglet.

Valproic acid is a commonly used drug for the treatment of epilepsy. Since valproic acid can only be given orally, its absorption from the gastrointestinal (GI) tract especially in patients with short bowel syndrome (SBS) and in neonates is important. The specific sites of absorption for valproic acid in the small intestine and colon have not been investigated. It is currently unknown whether these patients are able to absorb oral valproic acid sufficiently to maintain a therapeutic serum concentration. The primary objectives of the study were to: (a) determine the relative absorption of valproic acid from specific sites in the GI tract; and (b) investigate the influence of intestinal development on valproic acid absorption using the newborn piglet as a model. Two groups were studied: Group I included 5 piglets 18-21 days of age, and Group II included 5 piglets 1-3 days of age. A valproic acid solution was simultaneously perfused through 5 partitioned segments of the gastrointestinal tract: the duodenum, jejunum, ileum, right colon and left colon. Tritiated [3H] polyethylene glycol was co-administered to monitor water movement across the GI mucosa. Following steady state, samples were collected from each segment, and analyzed by a specific enzyme-mediated immunoassay. The absorption rates (micrograms/min/cm) of valproic acid in Group I were as follows: 9.96 +/- 2.8 duodenum; 11.28 +/- 2.79, jejunum; 9.42 +/- 3.34, ileum; 10.88 +/- 3.35, right colon; 10.96 +/- 2.92, left colon.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gastric and intestinal absorption of oxprenolol in humans

The gastrointestinal absorption of the beta blocker oxprenolol was investigated in four healthy subjects by an intubation technique. Oxprenolol was introduced into the stomach, dissolved in a homogenized meal containing the marker 14C-polyethylene glycol (PEG) 4000. Unlabeled PEG 4000 was perfused during the whole experiment into the duodenum at the ampulla of Vater. Samples of luminal contents were collected at regular intervals over four hours in the stomach, at the angle of Treitz, and 30 cm below this point. Blood was also collected. Oxprenolol was not absorbed in the stomach. About 80% of the drug emptied from the stomach was absorbed in the duodenum, and 80% of that released from the duodenum was absorbed in a 30-cm segment of the jejunum. The amounts absorbed in these two intestinal segments were directly proportional to the amounts delivered. The areas under the plasma concentration-time curves were not related to the amounts absorbed. A single dose of oxprenolol taken with an homogenized meal did not modify the gastric emptying and secretory response.     

甲基斑蝥胺在大鼠胃肠道的吸收动力学

目的研究甲基斑蝥胺(MCD)在大鼠胃及肠道的吸收动力学特征。方法采用封闭灌注技术进行原位胃灌注吸收研究,在体循环法考察小肠全肠段吸收,采用单向肠灌流技术进行不同肠段吸收研究,建立HPLC法测定MCD的浓度,考察MCD大鼠胃肠吸收特征及吸收机制。结果 116.34mg·L~(-1)MCD在十二指肠、空肠、回肠、结肠及胃中的吸收速率常数(K_a)分别为(0.0635±0.0091)、(0.0687±0.0008)、(0.0315±0.0009)、(0.0399±0.0009)和(0.0033±0.0001)min~(-1),不同药物浓度59.55、116.34、204.15mg·L~(-1)时胃及空肠中的K_a分别为(0.0031±0.0001)、(0.0033±0.0001)、(0.0031±0.0001)min~(-1)及(0.0667±0.0010)、(0.0687±0.0008)、(0.0705±0.0011)min~(-1);在空肠不同pH值(5.0,6.2,7.4)时K_a分别为(0.0801±0.000 9)、(0.0783±0.0009)、(0.0758±0.0009)min~(-1)。MCD在胃中吸收很弱;在空肠、十二指肠、结肠和回肠中均有一定吸收,在空肠吸收最好,在肠中吸收呈一级动力学过程,吸收机制为被动扩散。MCD溶液浓度及pH值对其肠吸收速率无显著影响(P>0.05)。结论 MCD属于生物药剂学分类系统Ⅰ类药物。     

The biodistribution and metabolic fate of [11C]acrylic acid in the rat after acute inhalation exposure or stomach intubation

Rats were nose-exposed to an atmosphere containing gaseous [11C]acrylic acid for 1 min and sacrificed 1.5 and 65 min later. At 1.5 min 28% of the administered radiolabel was associated with the snout of the exposed animal. The biodistribution data indicated the gastrointestinal tract as the major site of absorption of acrylic acid after inhalation exposure. Therefore, rats were also stomach intubated with an aqueous solution of [11C]acrylic acid and sacrificed at 1.5, 10, 20, 40, and 65 min after intubation. The absorption of acrylic acid from the stomach was rapid, as was its subsequent metabolism. Carbon-11 was rapidly eliminated from both nose-exposed and stomach-intubated animals as 11CO2, with about 60% of the administered dose eliminated 1 h after administration. A portion of the radiolabel was also eliminated via the renal system.     

Effects of capsaicin on intestinal cephalexin absorption in rats

The effects of capsaicin on intestinal cephalexin absorption were investigated by means of in situ single pass perfusion in rats to clarify whether this pungent compound present in spice is a potential factor altering the intestinal drug absorption processes. Under the control condition, cephalexin was absorbed at a rate of 1.16+/-0.08 and 0.90+/-0.06 nmol/min/cm in the jejunum and ileum, respectively. The intestinal cephalexin absorption rate was decreased when capsaicin was dissolved in the perfusate at a concentration of 400 microM, being 0.54+/-0.07 and 0.46+/-0.10 nmol/min/cm in the jejunum and ileum, respectively. The inhibitive effect of capsaicin on intestinal cephalexin absorption was diminished when ruthenium red, a non-selective inhibitor of the transient receptor potential (TRP) cation channels, was intravenously infused into the rat during the experiment. Moreover, when we evaluated the paracellular permeability of cephalexin by utilizing a competitive inhibitor, glycylsarcosine, it was demonstrated that glycylsarcosine-insensitive intestinal cephalexin absorption in the jejunum was increased by 4.5 times in the presence of 400 microM capsaicin. These findings indicate that capsaicin affects both transcellular and paracellular pathways of intestinal cephalexin absorption by interacting with the TRP cation channels in intestinal tissues, in which capsaicin seems to change the transport activity of H+/peptide co-transporter 1 (PEPT1), and to a lesser degree, it seems to alter the paracellular permeability of the intestinal epithelia.