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PubMedDate not supplied

Rectal drug administration: clinical pharmacokinetic considerations.

The human rectum represents a body cavity in which drugs can be easily introduced and retained and from which absorption is well possible. There are important therapeutic reasons why it is sometimes preferable to give a drug rectally rather than orally, e.g. in cases of nausea and vomiting. Drawbacks of rectal drug administration include the interruption of absorption by defaecation and lack of patient acceptability. The mechanism of drug absorption from the rectum is probably no different to that in the upper part of the gastrointestinal tract, despite the fact that the physiological circumstances (e.g. pH, fluid content) differ substantially, Absorption from aqueous and alcoholic solutions may occur very rapidly, which has proved to be of considerable therapeutic value in the rapid suppression of acute convulsive attacks by diazepam (e.g. in children), but absorption from suppositories is generally slower and very much dependent on the nature of the suppository base, the use of surfactants or other additives, particle size of the active ingredient, etc. There is some evidence that hepatic first-pass elimination of high clearance drugs is partially avoided after rectal administration, e.g. lignocaine. This can be explained by the rectal venous blood supply: the upper part is connected with the portal system, whereas the lower part is directly connected with the systemic circulation. Plasma concentration data following rectal administration of representatives of several classes of drugs are reviewed: anticonvulsants, non-narcotic analgesics and non-steroidal anti-inflammatory agents, hypnosedatives and anaesthetics, strong analgesics, theophylline and derivatives, corticosteroids, antibacterial agents, thiazinamium, promethazine, hyoscine-N-butyl-bromide, streptokinase, progesterone, ergotamine tartrate and levodopa. Only limited number of cases has it been adequately shown that the rectal route of administration gives plasma concentrations which are comparable to the oral route. Potentially the rectal route offers the same possibilities as the oral route, but the influence of the formulation seems to be very critical. It is also likely that the future novel drug delivery systems with zero order release characteristics will be applied rectally. Interesting preliminary results have already been obtained with theophylline administered by 2ml osmotic pumps.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Intestinal absorption of low molecular weight heparin in animals and human subjects.

INTRODUCTION: We had previously shown that the use of bile salts, which act as surfactants, facilitates the intestinal absorption of large molecules such as those of heparin and insulin. However, the bioavailability of unfractionated heparin (UFH) administered through the large intestine was low. The aim of the present study was to evaluate the absorption of low molecular weight heparin (LMWH) combined with bile salts through the gut mucosa in animals and human subjects. MATERIALS AND METHODS: LMWH (Fragmin, Kabi-Pharmacia, Stockholm) or UFH with or without sodium cholate (Sch) was administrated rectally in rats and healthy volunteers via a microenema. Absorption was estimated by the activated partial thromboplastin time (aPTT), the plasma anti-factor Xa activity and the plasma lipoprotein lipase (LPL) activation. RESULTS: In groups of 6 rats, LMWH at doses of 100--1,000 U with sodium cholate (10--20 mg/ml) was readily absorbed through the gut mucosa, as indicated by both, anti-factor Xa levels of up to 1 U/ml and a dose-dependent activation of LPL. The absorption was significantly superior to that of UFH with Sch or LMWH given without Sch (p < 0.001). The plasma anti-factor Xa levels in the 6 healthy volunteers who received a microenema containing 25,000 U of LMWH with 20 mg/ml of Sch were 0.38 U/ml at 15 min and 0.1 U/ml at 240 min. LPL activation and aPTT prolongation were also observed in these subjects. The plasma LMWH levels after rectal application were in the same range as those obtained after subcutaneous administration, however the elimination time (t 1/2) was shorter. There were no adverse reactions. CONCLUSIONS: Intestinal absorption of LMWH facilitated by Sch is both feasible and safe. A slow release formulation will be needed to prolong the plasma half-life.

Administration, Rectal↗
PubMed1988

Paths of ion transport across canine fetal tracheal epithelium.

Fluid secretion by the fetal sheep lung is thought to be driven by secretion of Cl- by the pulmonary epithelium. We previously demonstrated Cl- secretion by tracheal epithelium excised from fetal dogs and sheep. In this study we characterized the ion transport pathways across fetal canine tracheal epithelium. The transport of Na+ and Cl- across trachea excised from fetal dogs was evaluated from transepithelial electrical properties and isotope fluxes. Under basal conditions the tissues were characterized by a lumen-negative potential difference (PD) of 11 mV and conductance of 5.2 mS/cm2. The short-circuit current (Isc) was 43 microA/cm2 (1.6 mueq.cm-2.h-1). Basal Na+ flows were symmetrical, but net Na+ absorption (1.1 mueq.cm-2.h-1) could be induced by exposure of the luminal surface to amphotericin B (10(-6) M). Bilateral replacement of Na+ reduced Isc by 85%. Replacement of submucosal Na+ or exposure to submucosal furosemide (10(-4) M) reduced net Cl- secretion by 60-70%. Luminal exposure to indomethacin (10(-6) M) induced a 50% decrease in Isc, whereas isoproterenol (10(-6) M) increased Isc by 120%. The properties of the Cl- secretory pathway across fetal dog trachea are consistent with the model proposed for Cl- secretion across adult dog trachea and other Cl- -secreting tissues (e.g., bullfrog cornea and shark rectal gland). The absence of basal Na+ absorption by fetal dog trachea probably reflects limited apical membrane Na+ permeability.

Amphotericin B↗
PubMed2000

Plasma exudation, hyperaemia, and epithelial permeability in rats with oxazolone-induced colitis: modulatory effects of budesonide.

BACKGROUND: Oxazolone-induced colitis in the rat is an immune-driven model of human colitis. The aim of the present study was to measure the changes in the absorptive and exudative permeabilites, oedema formation, and local blood flow in this model during the development of inflammation. We also assessed the effects of acute (<1 h), topical glucocorticosteroid (GCS) treatment on these factors. METHODS: Colitis was induced by local instillation of oxazolone in previously sensitized animals. Calculating the 40-min plasma-equivalent extravascular volume quantitated the plasma exudation rate. This was determined by using labelled albumin as marker for total tissue content of plasma and Evans blue content as marker for the intravascular volume. Absorptive permeability was simultaneously measured as uptake of rectally administered (51Cr)-labelled ethylenediaminetetraacetic acid (EDTA). In separate experiments regional blood flows were measured by means of the labelled microsphere method. RESULTS: At both 3 and 24 h after challenge marked enhancements of both exudative and absorptive permeabilities were found. At 24 h there was also an increase in local blood flow. GCS treatment abolished all of the hyperaemia and the main part of the exudative response but had no significant effect on the absorptive permeability. CONCLUSIONS: In this model immunologic mechanisms induce permeability and blood flow changes similar to those in the human disease. It seems suitable for the study of GCS and other anti-inflammatory or immune-modulating drugs.

Administration, Topical↗
PubMedDate not supplied

[Drug administration through the rectum: reliability, tolerance].

The main form of rectal administration of medications is the suppository. The rapidity of release of the active principle in the rectal fluid depends mainly on the physicochemical properties of the vehicle. Absorption per se is influenced by the liposolubility as well as the ionization of the medication, and by the site of its release since only the middle and inferior hemorrhoidal veins avoid the hepatic crossing. For molecules subjected to a major 1st hepatic crossing (lidocaine, propranolol, ergotamine...), pharmacokinetic studies demonstrate that the rectal route enables to obtain a bioavailability which is markedly higher by oral route, and plasma concentrations at a therapeutic level. The use, still experimental, of rectal osmotic pumps, provides balanced plasma concentrations which remain stable during the entire duration of the application. Undesirable side effects related to the administration of drugs via the rectal route, are, most of the time, local ones. The vehicles seem to be responsible for diffuse ano-rectitis. Cases of rectal ulcerations with necrosis have been reported following the excessive use of suppositories containing dextro-propoxyphene or ergotamine.

Administration, Rectal↗
PubMedDate not supplied

[Physiologic nutrition studies in swine with ileorectal anastomoses. 2. The effect of nourseothricin on nutrient digestibility, amino acid absorption, protein utilization and mineral balance of a rye diet].

The supplement of nourseothricin (NT) to a rye diet did not have an influence on the precaecal and total apparent digestibility of the crude nutrients or the total digestibility of the amino acids (AA). NT produced significantly higher absorption of some AA in pigs with ileo-rectal anastomoses (IRA) which were orally supplied with electrolyte solution (ES). In general, IRA pigs showed the same results with regard to precaecal apparent AA absorption influenced by the AA pattern of endogenous protein as pigs with ileal cannulae. Functions in the large intestine seem to be important for the effect of NT supplements, as NT supplements to the diet of intact animals tendentially had a positive effect on N, Ca and P balances, IRA animals, however, showed a contrary effect. In comparison with the intracaecal infusion of ES, the oral supply of the IRA pigs resulted in higher N, Ca and P balances. The level of N utilization (N balance in % of the digested N) of the IRA pigs supplied orally was equally high as that of the intact animals (both groups without NT). As derives from literature and the available N, Ca and P balances--significantly influenced by ES supplements--an additional supplement of rations poor in crude fibres of 1 g Na/animal and day seems sufficient for covering the requirement of IRA pigs of a weight of 30...40 kg. After 18 days a P supply below the requirement resulted in a significantly reduced P level (inorganic) in the serum in both animal groups, with the level of the IRA pigs being significantly below that of the INT animals. For this reason, the P requirement of fattening pigs should be fully covered in experiments with IRA pigs. Although the IRA pigs supplied caecally with ES showed typical appearances of Na deficiency, their Na level in the serum did not differ from that of the other animals.

Amino Acids↗
PubMed1981

Bioavailability of phenobarbital by rectal administration.

Phenobarbital was administered to five patients, eight to 20 years of age, by four different administration routes: Intravenous, intramuscular, oral, and rectal. At each administration, extent of bioavailability, elimination rate constant, absorption rate constant, and volume of distribution of phenobarbital were calculated using a one-compartment open model. The results obtained suggest that rectal administration of phenobarbital is more reliable than intramuscular or oral administration of the drug for rapid treatment in children.

Adolescent↗
PubMed1978

[Investigations concerning temperature and serum concentrations of paracetamol in febrile infants following rectal application of paracetamol (author's transl)].

If paracetamol as an antipyretic is applied as suppository, absorption is much slower than after oral application. With the same dosage serum concentrations are lower after rectal application than after oral. It is necessary to give nearly twice the dose using rectal rather than oral application to reach the same antipyretic effect. The duration of efficacy is longer after rectal application because serum concentrations decline slower.

Acetaminophen↗
PubMed2000

Putting rectal 5-aminosalicylic acid in its place: the role in distal ulcerative colitis.

Oral aminosalicylates such as sulfasalazine and mesalamine are widely prescribed for the treatment of mild or moderately active distal ulcerative colitis. However, a critical review of the literature demonstrates that rectal 5-aminosalicylic acid (5-ASA) is the optimal therapy for this disease. Meta-analyses of published trials show that rectally delivered 5-ASA is superior to placebo and to conventional rectal corticosteroids in inducing remission of distal ulcerative colitis, whereas the combination of rectal 5-ASA with a rectal corticosteroid or oral aminosalicylate is superior to rectal 5-ASA alone. For maintaining remission of distal ulcerative colitis, rectal 5-ASA is significantly better than placebo and at least as effective as oral 5-ASA. The dosage forms available for rectal delivery include suppositories, foams, and liquid enemas, and selection among these preparations should be guided by the proximal extent of disease and patient preference. The efficacy of rectal 5-ASA is complemented by its low rate of reported adverse effects, which may reflect its reduced potential for systemic absorption. This review summarizes the evidence supporting the role of rectal 5-ASA as a first-line therapy for mild or moderately active distal ulcerative colitis, and offers guidelines for its use.

Administration, Oral↗
PubMedDate not supplied

Measurement of glucose and water transport in the human duodenum in vivo using a dialysis bag.

BACKGROUND/AIMS: Only a few studies have evaluated duodenal absorptive or secretory function in humans. In the present study we determined duodenal glucose and water transport in humans in vivo. MATERIAL AND METHODS: Duodenal glucose and water transport were studied in 27 healthy volunteers using a modification of the dialysis bag technique for measuring rectal water and sodium transport. RESULTS: Net glucose absorption increased progressively over the range of glucose concentrations studied (10 mM to 100 mM) from 0.21 +/- 0.19 to 1.76 +/- 0.15 mM/cm2/90 min. Maximum water absorption occurred from the 10 mM glucose solution (35.87 +/- 7.5 microliters/cm2/90 min) and at a significantly greater rate than from the 80 mM glucose (11.60 +/- 4.0 microliters/cm2/90 min) and the 100 mM glucose (14.90 +/- 1.7 microliters/cm2/90 min solution. CONCLUSION: This study demonstrates that glucose and water are absorbed by the human duodenum in vivo and that the dialysis bag technique can be adapted to measure transport processes in areas of the intestine other than the rectum.

Adult↗
PubMed1981

Bioavailability of rectal aspirin in neurosurgical patients.

Serum salicylate levels were determined fluorimetrically in 12 neurosurgical patients after rectal and oral administration of 1.0 g aspirin. There was no significant difference in the AUC-value between the two routes of administration, but a slower rate of absorption with no clear peak effect was found after rectal administration. Rectal aspirin is useful in clinical situations in which mediation is difficult by the oral route, e.g. after neurosurgical and open-heart surgical interventions.

Administration, Oral↗
PubMed1989

Colonic absorption of insulin: an in vitro and in vivo evaluation.

Rectal administration of insulin as a suppository or p.o. administration of a proteolysis-resistant insulin analog lowers serum glucose levels, suggesting uptake and/or diffusion of intact insulin across the epithelium of the large intestine; however, no rigorous studies of insulin degradation and/or transepithelial flux in vitro have been reported with isolated colonic epithelium. Everted and noneverted sacs of rat distal colonic epithelium were prepared and incubated at 37 degrees C with porcine [125I]insulin and less than 1% of the [125I]insulin crossed the epithelial barrier under these in vitro conditions. The apical surface degraded [125I]insulin at a rate of 0.071 fmol/mg of dry wt./min, whereas the submucosal surface degraded insulin at a rate of 0.045 fmol/mg of dry wt./min. Over 60% of the available [125I]insulin was degraded by the apical surface of the distal colon during a 15-min incubation, whereas approximately 40% of the radioligand was degraded by the submucosal surface under identical conditions. Degradation of [125I]insulin was inhibited partially by the addition of excess unlabeled insulin and inhibited completely by the addition of bacitracin (1 mg/ml). These results indicate that the mammalian colonic epithelium is an effective barrier to transepithelial flux of insulin and identify insulin-degrading activity on both the apical and submucosal surfaces of the colonic epithelium. Although the colonic epithelium represents a significant physiological barrier to the uptake of insulin from the intestinal lumen, paradoxically, administration of large doses of unlabeled insulin into the distal colon or into the entire large intestine caused a dose-dependent increase in serum insulin levels during a 15-min experiment in vivo.

Animals↗
PubMed1988

The effect of metoclopramide and prochlorperazine on the absorption of effervescent paracetamol in migraine.

Antiemetics modify gastric emptying, a rate-limiting step in drug absorption. The absorption of effervescent paracetamol in water solution was studied in three groups of 10 female patients during acute migraine attacks. Paracetamol was preceded 30 min earlier by a rectal dose of metoclopramide, prochlorperazine maleate, or placebo. Each patient was retested with paracetamol when headache-free. Migraine attacks delayed slightly the absorption of paracetamol solution. Prior administration of rectal prochlorperazine had a minor delaying effect on paracetamol absorption. The peak concentration, the time to reach the peak, and the area under the time-concentration curve from 0 to 6 h of paracetamol were similar with the three treatments.

Acetaminophen↗
PubMed1991

The influence of rectal cisapride on morphine-induced gastric stasis.

The effect of a new formulation of the gastric prokinetic agent cispride on opioid-induced gastric stasis was investigated. Forty patients were randomly allocated to one of four therapies administered as premedication; group A, placebo suppositories only; group B, placebo suppositories and intramuscular morphine 10 mg; group C, rectal cisapride 30 mg and intramuscular morphine 10 mg and group D, rectal cisapride 60 mg and intramuscular morphine 10 mg. Gastric emptying was assessed from the small bowel absorption of paracetamol following oral absorption. The kinetics of the suppository formulation were determined from venous blood samples. Rectal cisapride in the two doses used did not prevent opioid-induced gastric stasis. This may reflect an inability of this formulation to produce adequate plasma concentrations.

Acetaminophen↗
PubMed1980

Cryptonephric malpighian tubule system in a dipteran larva, the New Zealand glow-worm, Arachnocampa luminosa (Diptera: Mycetophilidae): a structural study.

The Malpighian tubules of the glow-worm are divided into four morphologically distinct regions, each composed of a different cell type. Part 3 of the Malpighian tubules of A. luminosa is intimately bound to the rectum by a layer of fat body. This association of the tubules with the hindgut is referred to as a cryptonephric system. This type of arrangement has been described in some Coleoptera and the larvae of most Lepidoptera but has never before been reported in the Diptera. In the glow-worm the cryptonephric tubules themselves are small, and adjacent to the fat body the epithelial cells are modified to form very thin windows or 'leptophragmata' (Lison, 1937). The main epithelial cells exhibit features characteristic of highly active, secretory Malpighian tubule cells. The high density of mitochondria and their association with all the microvilli is indicative of a highly active secretory cell. The high concentration of glycogen in these cells and their intimate association with the hindgut suggest that they may, in addition, have a nutrient absorptive function. The role of the cryptonephric rectal complex in the glow-worm is discussed in the light of present knowledge gained from previous studies of coleopteran and larval lepidopteran cryptonephric systems. On structural grounds a model is proposed for the regulation of the ionic environment of the rectum, and the uptake and metabolism of organic material from the rectal lumen by this cryptonephric complex.

Animals↗
PubMed1993

Methadone in the management of cancer pain: a review.

Methadone is a synthetic opiate receptor agonist that has been available for more than 40 years. Although its main use has been in the maintenance treatment of opioid addicts, it has excellent analgesic effects and low cost. Its use is limited by its long and unpredictable half-life and by the limited knowledge of the most appropriate method for titration and interval of administration. Most reports on this drug are uncontrolled and limited to a small number of patients receiving low doses of methadone. Methadone should be titrated carefully and individualized doses and intervals should be determined for each patient. Future research should attempt to determine the equi-analgesic dose for chronic use, its effectiveness and tolerance when used in high doses, and its absorption and tolerance using alternative routes, e.g., rectal and subcutaneous.

Humans↗
PubMed2006

Drinking in juvenile Atlantic salmon (Salmo salar L.) in response to feeding and activation of the endogenous renin-angiotensin system.

Drinking rate and rectal fluid production of juvenile Atlantic salmon (1-2 g) in freshwater were investigated in unfed fish and recently fed fish. Drinking was also investigated following activation of the renin-angiotensin system (RAS) by two hypotensive agents, a nitric oxide (NO) donor sodium nitroprusside (SNP) and bacterial lipopolysaccharide (LPS). In unfed fish the basal drinking rate was 0.13 microL g(-1) h(-1) and rectal fluid production was 0.076 microL g(-1) h(-1). In recently fed fish both drinking rate and rectal fluid production increased significantly by about fivefold compared to unfed fish, and similar values were obtained for fish exposed to PS for 24 h. Exposure to SNP resulted in about a tenfold elevation of drinking rate and rectal fluid production, compared to unfed fish. Absorption of water by the gut was in the range 35-60% for all treatments. Drinking may have a role in processing food in the gut and the fluid in the gut may subjected to absorptive and secretory processes. The most likely route for removal of water absorbed by the gut is excretion via the kidney and this would result in an increased osmoregulatory burden on the fish. In polluted waters drinking could be increased through stimulation of the endogenous RAS by vasodilators, e.g., LPS and the gut could be a significant target for toxin exposure.

Animals↗