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PubMed1987

Bioavailability of progesterone with different modes of administration.

The bioavailability of micronized progesterone (P) was studied by measuring sequential serum P concentrations after a single bolus of 50-200 mg P given sublingually, orally (capsule and tablet), vaginally and rectally (suppositories) during the follicular phase in a group of normally menstruating women. When compared to other modes of P administration, the area under the curve during the first eight hours was twice as high with the rectal route. With 50 and 100 mg P given sublingually and 100 and 200 mg ingested as tablets, peak levels and area under the curve were twice as high with the higher dosage. The response was more sustained with the higher dosage. All subjects exhibited a significant increase in serum P levels over baseline that persisted for at least eight hours. P levels were still increased over baseline at 24 hours in all subjects after the administration of 100-mg vaginal and rectal suppositories and 200-mg tablets. These findings are in general agreement with previous reports showing that luteal phase serum P concentrations can be reached easily with non-parenteral modes of administering micronized P and that oral P administration could become an attractive alternative to the currently used oral mode of administering synthetic progestins.

Absorption↗
PubMed2002

Comparative absorption of 5-aminosalicylic acid (5-ASA) after administration of a 5-ASA enema and salazosulfapyridine (SASP) after an SASP suppository in Japanese volunteers.

Salazosulfapyridine (SASP) is widely used orally and rectally in the treatment of ulcerative colitis. SASP is mainly metabolized by hydrolysis and the main active metabolite, 5-aminosalicylic acid (5-ASA), has an antiinflammatory effect. In the present study, we prepared suppositories containing 6.5 mmol of SASP and an enema containing 6.5 mmol of 5-ASA. We measured the concentrations of SASP and its various metabolites, 5-ASA, sulfapyridine (SP), acetylated metabolite of SP (Ac-SP), and N-acetyl-5-ASA (Ac-5-ASA), in the serum and urine after a single administration of each preparation to healthy male volunteers. When the SASP suppository was administered, the maximum concentration (Cmax) of SASP and Ac-5-ASA was 2.5+/-0.4 and 0.5+/-0.2 microM and the time to Cmax (Tmax) was 5 and 12 h, respectively. The Cmax value of SP, which causes side effects, was one-half of that of the parent compound. No 5-ASA in the serum was observed. When the 5-ASA enema was administered, Cmax and Tmax values of 5-ASA and Ac-5-ASA were 5.8+/-2.0 and 13.3+/-3.6 microM and 1 and 7 h, respectively. The area under the serum concentration-time curve (AUC) of SASP was 27.4+/-4.8 microM x h, a finding similar to that of 5-ASA after the administration of the 5-ASA enema (29.4+/-11.1 microM x h). The percentage of urinary recovery of SASP 24 h after administration of the SASP suppository was approximately 0.2%. These results indicate that SASP administered rectally is almost completely hydrolyzed in the colon and that 5-ASA is partially absorbed from the small intestine in unchanged form. On the other hand, approximately 0.3% of 5-ASA was recovered in the urine in unchanged form after the administration of the 5-ASA enema, whereas the urinary recovery of Ac-5-ASA was more than 10%. The present findings suggest that 5-ASA has favorable absorptive properties and can be expected to have systemic action after rectal administration of a 5-ASA enema.

Absorption↗
PubMed1987

Effect of hypothermia on the intestinal absorption of uracil and L-dopa in the rat.

The in situ rat gut technique was used to explore the effects of hypothermia on the intestinal absorption of L-dopa and uracil. A hypothermic state was induced when male Sprague-Dawley rats, weighing between 300 and 370 g, were exposed to an atmosphere of helox (helium:oxygen, 80:20) at 0-4 degrees C. After 4 to 5 h, the rectal temperatures were decreased from 37 to 20 degrees C. The rewarming process for hypothermic animals undergoing anesthesia appears to be prolonged. The animals were prepared for surgery using ether as anesthetic after a rectal temperature of 20 degrees C was attained. Hypothermia showed a significant influence on decreasing L-dopa and uracil disappearances from the intestinal lumen. About 40 percent reduction of the rates of disappearance was observed with a 10 degrees C reduction of the rectal temperature. Additionally, a rapid drop of the rate of drug disappearance was observed in the beginning stage of rectal temperature decrease (31-36 degrees C) as well as in the hypothermic state with rectal temperatures < 26 degrees C. There appears to be a thermal stable region for absorption between 26 and 30 degrees C. Water efflux was studied in both normothermic and hypothermic animals. Normothermic rats showed greater average cumulative water efflux over a period of 30 min (71 and 61% for L-dopa and uracil, respectively) in comparison with that of hypothermic rats (34 and 41% for L-dopa and uracil, respectively). The cold-treated animals showed decreased rates of disappearance associated with the decreased water efflux. Therefore, the reduction of the rates of drug disappearance from the intestinal lumen caused by hypothermia may be partially related to the decrease of water efflux during hypothermia.

Animals↗
PubMed1998

Mechanical, histologic, and biochemical effects of canine rectal formalin instillation.

UNLABELLED: Instillation of 4 percent formalin effectively treats radiation hemorrhagic proctitis; however, little is known regarding its side effects. PURPOSE: The study contained herein was undertaken to determine rectal compliance and collagen content, mucosal and vascular histologic changes, and kinetics of formalin absorption following instillation. METHODS: Fifteen mongrel dogs (50-60 pounds) were randomized into five experimental groups according to time elapsed from formalin treatment: control, acute, one week, two weeks, and four weeks. Formalin was instilled in 30-ml aliquots to a total volume of 400 ml. Rectal compliance (closed manometry system) was assessed pre-formalin and post-formalin at the designated time interval. Serum formalin metabolites were determined at time 0, 0.5, 1, and 3 hours. A segment of rectal wall was analyzed for collagen content, mucosal injury, and blood vessel density. RESULTS: Serum formalin levels peaked within 30 minutes, returning to normal by 3 hours. With the exception of one dog, toxic levels were not reached at any time during the study. No dogs experienced sepsis, fever, or altered gastrointestinal function. Acute and one-week dogs showed mild diffuse proctitis and mucosal slough, which healed within two weeks. Rectal compliance and collagen content were unchanged. Mucosal blood vessels decreased in number early (P = 0.03). CONCLUSIONS: Instillation of 4 percent formalin in sequential aliquots of a small volume that is kept in contact for a short period of time is safe. Serum formalin levels generally do not reach toxic levels, and the slight elevation in formalin concentration that was seen returns to normal within three hours. Formalin-induced proctitis heals within two weeks, and no long-term changes in rectal compliance or collagen content were seen.

Administration, Rectal↗
PubMed1995

Pharmacokinetic and pharmacodynamic studies of a thromboxane synthetase inhibitor, ozagrel, in rabbits.

The pharmacokinetic and pharmacodynamic (PK/PD) characteristics of ozagrel, a new potent and selective thromboxane synthetase inhibitor, were investigated in rabbits after its intravenous, oral, and rectal administration. Serum level of TXB2 (the stable metabolite of TXA2), a direct pharmacological marker, was measured after each dosing. A marked reduction of serum TXB2 within 30 min was shown after the three routes of administration, reflecting rapid onset of action. Due to rapid and complete absorption (i.e., Tmax; 20 min, bioavailability; 100%) and longer duration of pharmacological action after rectal dosing, the rectum offers a practical delivery route for ozagrel. An Emax model was employed to fit the pharmacological data, and IC50 and Emax for thromboxane synthetase inhibition were estimated to be 56.0 ng/ml and 94%, respectively. These pharmacodynamic parameters were incorporated into an integrated mathematical model to simulate the PK/PD profiles of ozagrel after i.v., oral, and rectal administration at lower (50 mg) and higher (200 mg) doses, and good agreement between the experimental and calculated values was achieved. The present PK/PD model may be useful for optimizing the therapeutic regimens of ozagrel.

Administration, Oral↗
PubMed1996

Effects of acarbose on fecal nutrients, colonic pH, and short-chain fatty acids and rectal proliferative indices.

Acarbose, an alpha-glycosidase inhibitor, treats diabetes mellitus by delaying the digestion and intestinal absorption of dietary carbohydrates. In effective doses, acarbose induces some passage of carbohydrates into the colon. The effect of such chronic carbohydrate transfer on colonic structure and function is unknown. We studied the effects of 1 year of acarbose administration in diabetes mellitus on fecal energy, protein, and fat, including short-chain fatty acids (SCFA) output, fecal pH, and several metabolizing bacterial species. Changes in colonic histology and epithelial cell proliferation were investigated in rectal biopsies. Fecal macronutrient output was unaffected by acarbose, but pH decreased and total SCFA, butyrate, and acetate output were markedly greater. Breath hydrogen output increased after acarbose, but digoxin-metabolizing bacteria and diacylglycerol (DAG) production were unaltered. Compared with the control, acarbose did not induce hyperplasia or change rectal proliferation. However, total fecal SCFA and butyrate output correlated inversely with proliferation in the rectal upper crypt-a biomarker of risk for colonic neoplasia. In conclusion, long-term acarbose administration does not adversely affect colonic function or fecal nutrient output. If increased fecal SCFA and butyrate reduces upper-crypt proliferation, then acarbose may reduce the risk of colonic neoplasia.

Acarbose↗
PubMed2006

Water vapour absorption in the penicillate millipede Polyxenus lagurus (Diplopoda: Penicillata: Polyxenida): microcalorimetric analysis of uptake kinetics.

The aberrant millipedes of the order Polyxenida are minute animals that inhabit xeric microclimates of bark and rock faces. The lichens and algae that provide their main food substrates tolerate extensive dehydration, effectively eliminating a liquid water source during periods of drought. In this study, we used microcalorimetry to test whether Polyxenus lagurus (L.) exploits active water vapour absorption (WVA) for water replenishment. Individual animals were pre-desiccated to 10-20% mass-loss and heat fluxes then monitored using a TAM 2277 microcalorimeter. The calorimetric cell was exposed to an air stream increasing progressively in humidity from 84% to 96%. WVA was distinguishable as large exothermic fluxes seen in > or = 86% RH. Owing to very small and opposing heat fluxes from metabolism and passive water loss, the measured flux provided a good measure of water uptake. WVA showed an uptake threshold of 85% RH and linear sorption kinetics until >94% RH, when uptake became asymptotic. Uptake was rapid, and would allow recovery from 20% dehydration (by mass) in little over 5 h. The uptake flux scales proportional, variant mass (0.61), suggesting an area-limited mechanism. Polyxenus possesses a cryptonephric system, analogous to that of tenebrionid beetle larvae. Measurements of water absorption and desorption from faecal pellets voided in different humidities gave an estimated rectal humidity of 85.5%. The close congruence between this value and the WVA threshold provides evidence for a cryptonephric uptake mechanism derived independently from that of tenebrionids. Polyxenus represents the first documented example of WVA in the myriapod classes.

Absorption↗
PubMed2002

A pilot study of topical intrarectal application of amifostine for prevention of late radiation rectal injury.

PURPOSE: Clinical symptomatic late injury to the rectal wall occurs in about one-third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of the prostate to the anterior rectal wall. On the basis of our previous observations in an animal model that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall, a Phase I dose-escalation clinical trial was undertaken. METHODS AND MATERIALS: Twenty-nine patients with localized prostate cancer were accrued. Eligibility criteria included histologically confirmed adenocarcinoma, Karnofsky performance status >or=70, and no pelvic lymphadenopathy or distant metastases. The total dose to the prostate was 70.2 Gy in 20 patients and 73.8 Gy in 9 patients. Therapy was delivered using a 4-field technique with three-dimensional conformal planning. Amifostine was administered intrarectally as an aqueous solution 30 min before irradiation on the first 15 days of therapy. Amifostine was escalated in cohorts from 500 to 2500 mg. Proctoscopy was performed before therapy and at 9 months after completion. Most patients underwent repeat proctoscopy at 18 months. On Days 1 and 10 of radiotherapy, serum samples were collected for pharmacokinetic studies. The clinical symptoms (Radiation Therapy Oncology Group scale) and a proctoscopy score were assessed during follow-up. RESULTS: All patients completed therapy with no amifostine-related toxicity at any dose level. The application was feasible and well tolerated. No substantial systemic absorption occurred. With a median follow-up of 26 months, 9 patients (33%) developed rectal bleeding (8 Grade 1, 1 Grade 2). At 9 months, 16 and 3 patients developed Grade 1 and Grade 2 telangiectasia, respectively. This was mostly confined to the anterior rectal wall. No visible mucosal edema, ulcerations, or strictures were noted. No significant differences were found between the proctoscopy findings at 9 and 18 months. Four patients (14%) developed symptoms suggestive of radiation damage that, on sigmoidoscopy, proved to be secondary to unrelated processes. These included preexisting nonspecific proctitis (n = 1), diverticular disease of the sigmoid colon (n = 1), rectal polyp (n = 1), and ulcerative colitis (n = 1). Symptoms developed significantly more often in patients receiving 500-1000 mg than in patients receiving 1500-2500 mg amifostine (7 [50%] of 14 vs. 2 [15%] of 13, p = 0.0325, one-sided chi-square test). CONCLUSION: Intrarectal application of amifostine is feasible and well tolerated. Systemic absorption of amifostine and its metabolites is negligible, and close monitoring of patients is not required with rectal administration. Proctoscopy is superior to symptom score as a method of assessing radiation damage of the rectal wall. The preliminary efficacy data are encouraging, and further clinical studies are warranted.

Adenocarcinoma↗
PubMed1991

The pharmacokinetics and colonic tissue concentrations of cyclosporine after i.v., oral, and enema administration.

This study compares pharmacokinetic parameters and colonic tissue concentrations of cyclosporine administered by olive-oil or water-retention enemas with conventional intravenous (i.v.) and oral dosing. Five medical students were enrolled in a prospective crossover study. All subjects received a single dose of cyclosporine on four separate occasions, once orally, once as an olive-oil enema, once as a water enema, and once i.v. Cyclosporine concentration was measured in blood and in colonic tissue obtained by flexible sigmoidoscopy. Bioavailability was 18 +/- 7% (mean +/- SD) for the oral dose and was unmeasurable for the oil and water enemas. The concentration of cyclosporine in colon tissue was 32,443 +/- 17,251 ng/g (mean +/- SD) for the i.v. dose, 2797 +/- 1812 ng/g for the oral dose, 21,727 +/- 14,090 ng/g for the oil enema, and 25,318 +/- 30,408 ng/g for the water enema. The authors conclude that the bioavailability of cyclosporine, and thus the systemic absorption after administration by a retention enema, is negligible. The colonic tissue concentration of cyclosporine after i.v. or rectal administration via an enema is tenfold higher than that for oral dosing. These findings suggest that cyclosporine-retention enemas produce high distal colonic tissue concentrations with negligible systemic absorption after a single dose in healthy subjects and should be evaluated as treatment for patients with left-sided colitis. Because cyclosporine administered by the i.v. route provided sharply higher colonic tissue concentrations than those seen with oral therapy, pulse i.v. cyclosporine should be tried for patients with severe ileitis and colitis.

Administration, Oral↗
PubMed1984

Decreased body weight in fetal rats after irradiation with 2450-MHz (CW) microwaves.

Female Sprague-Dawley (CD) rats were exposed to 2450-MHz (CW) microwave radiation at incident power densities of 0 or 40 mW/cm2 (SAR = 6.0 W/kg) for 100 min daily on the sixth through 15th day of gestation. One-time exposure to the same conditions increased average colonic temperatures 2 degrees C at the end of irradiation in pregnant rats of similar size. There were 23 sham-irradiated and 24 microwave-irradiated females. When these groups were compared on the 21st day of gestation, no significant differences were found in pregnancy rates; in the numbers of live, dead or total fetuses; nor in the incidences of external, visceral or skeletal anomalies or variations. However, mean fetal body weight was significantly (p = 0.0008) lower after microwave irradiation and was 9% less than that of sham-irradiated litters. Sternal ossification was also significantly delayed in the microwave-irradiated fetuses (p = 0.007). It is concluded that even though a change in the malformation rate is not effected in rats, a fetotoxic effect does occur due to microwave-exposure conditions which raise maternal rectal temperatures to approx. 40 degrees C and produce a specific absorption rate (SAR) greater than or equal to 6 W/kg in the dam.

Animals↗
PubMed1992

Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives.

Metronidazole was first introduced for the treatment of trichomoniasis. Its therapeutic use has subsequently been expanded to include amoebiasis, giardiasis and, more recently, anaerobic infections. Most of the early pharmacokinetic studies employed nonspecific assays such as microbiological and chemical assays. These assays were not able to differentiate the parent drug from the metabolites or other interfering substances. Pharmacokinetic data obtained through the use of specific chromatographic techniques provide the basis for this review of recent pharmacokinetic findings concerning metronidazole and other nitroimidazole antibiotics. When given intravenously or orally at usual recommended doses, metronidazole attains concentrations well above the minimum inhibitory concentrations for most susceptible micro-organisms. The drug has an oral bioavailability approaching 100%. Rectal and vaginal administration results in a smaller amount of drug absorption and lower serum concentrations. Metronidazole has limited plasma protein binding but can attain very favourable tissue distribution, including into the central nervous system. The drug is extensively metabolised by the liver to form 2 primary oxidative metabolites: the hydroxy and acetic acid metabolites. The kidney is responsible for the elimination of only a small amount of the parent drug; however, normal excretion of the 2 metabolites is dependent on the integrity of kidney function. The metabolism of metronidazole was found to vary among patient groups. Preterm and term infants have lower total body clearance (CL) and prolonged elimination half-lives. However, children older than 4 years old were observed to have pharmacokinetic parameters similar to those in adults. Reduced CL was also observed in children who are malnourished. Elderly patients have reduced renal excretion of both the parent drug and hydroxy metabolite. Pharmacokinetic parameters in pregnant patients were not significantly different from those in nonpregnant women; however, the drug is distributed into breastmilk and the infant will be exposed to the drug through the nursing mother. Patients undergoing gastrointestinal surgery or having enteric diseases and those who are hospitalised or critically ill also have altered pharmacokinetics. Metabolism of the drug is reduced in patients with liver dysfunction, giving delayed production of metabolites. In contrast, renal failure has little effect on the elimination of the parent drug, but affects the excretion of the metabolites more significantly. Haemodialysis was found to remove a substantial amount of the metronidazole while the effect of peritoneal dialysis was more limited. Energy and protein deficient diets as well as occupational exposure to gasoline did not alter metronidazole pharmacokinetics. However, the effect of alcohol consumption on metronidazole CL requires further study.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed2000

5-Aminosalicylic acid containing drugs. Delivery, fate, and possible clinical implications in man.

Since the beginning of the 1940s salazosulfapyridine (SASP) has been used in the treatment of chronic inflammatory bowel disease (CIBD). Almost 40 years later 5-aminosalicylic acid (5-ASA), which is split off by azo-reducing enzymes in the colon, was identified as the therapeutically active moiety of SASP. Thus different 5-ASA containing drugs were produced from which 5-ASA is released in the small and large intestine in a pH-dependent manner. Since there is a firm clinical indication that the 5-ASA concentration in the gut lumen is decisive for the therapeutic effect, a method was developed to evaluate the 5-ASA concentration at different levels in the intestine. The method was subsequently used to clarify factors of importance for the release of 5-ASA from the preparations. Ileostomy patients and healthy volunteers were investigated during continuous treatment with the three 5-ASA containing drugs with pH-dependent 5-ASA release: Asacol, Mesasal (Salofalk, Claversal), and Pentasa. The study confirmed release of 5-ASA in the small intestine from all preparations, but at different levels and speeds. Despite similar peroral dosage, very different 5-ASA concentration profiles were found in the ileostomy effluents, reflecting not only the difference in the release pattern of the preparations, but also the influence of the gastric residence time for larger sized tablets. The 5-ASA concentrations increased in the faeces of healthy volunteers. Furthermore the systemically absorbed fraction of 5-ASA was larger than previously found after SASP. The 5-ASA release from the preparation with the most proximal release, Pentasa, was less influenced by acceleration of the intestinal transit time than previously demonstrated after SASP in a similar study design. A comparative study of children given SASP and Pentasa showed similar results as in adults: a tendency for smaller 5-ASA concentration at rectal level after Pentasa than after SASP, and also larger systemic absorption. Despite higher 5-ASA dose per kg body weight, lower 5-ASA concentrations were seen in the faeces after both preparations, compared with adults. A peroral dose increase of Pentasa in healthy adults resulted in higher intraluminal 5-ASA concentration in the gut lumen, but also in saturation of the local and probably also systemic acetylation capacity, demonstrated by higher plasma concentrations and larger urinary excretion of 5-ASA. Similar faecal water concentrations were found after Pentasa 4 g and the azo-bond preparation with colonic 5-ASA release, Dipentum (olsalazine) 2 g, confirming the substantial 5-ASA release from Pentasa in the small intestine. Investigation of pregnant patients treated with different 5-ASA containing drugs showed a similar pattern to SASP treatment: small amounts of 5-ASA cross the placenta, whereas the concentration of the metabolite Ac-5-ASA is similar in the maternal and fetal circulations. Only minute amounts of 5-ASA were found in milk from nursing mothers, while the concentrations of Ac-5-ASA were considerably higher. The decrease in the semen quality during SASP treatment was improved by changing to a controlled-release 5-ASA drug. The concentrations of 5-ASA in seminal plasma were similar during the two treatment periods, but higher of its metabolite Ac-5-ASA during treatment with the controlled-release preparation. That indicates that the toxic effect after SASP is not caused by the 5-ASA or Ac-5-ASA moiety. All the preparations have proved effective in the treatment of ulcerative colitis, but data concerning the 5-ASA treatment of Crohn's disease are conflicting. Knowledge of the demonstrated differences in the release profiles of the 5-ASA containing drugs is therefore important when designing future clinical trials.

Administration, Oral↗
PubMed1987

Kinetics of rate controlled rectally administered ranitidine to male volunteers.

Ranitidine hydrochloride solution was given rectally to six healthy volunteers by means of an osmotic pump (Osmet) at a zero-order rate for 8 h. Quite constant steady-state drug concentrations were achieved in the range of 64-123 ng/ml plasma (mean Css: 100.6 ng/ml). The mean absorption time was 0.45 h (range 0-I.02 h), indicating that absorption was not always instantaneous. It is concluded that the Osmet system together with the rectal route offer the possibility for achieving steady-state concentrations of ranitidine, enabling the determination of pharmacodynamic effects. In addition, the rectal route can be considered as an alternative to oral and intravenous administration.

Administration, Rectal↗
PubMed1998

Thermally reversible xyloglucan gels as vehicles for rectal drug delivery.

The aim of this study was to investigate the potential application of thermoreversible gels formed by a xyloglucan polysaccharide derived from tamarind seed for rectal drug delivery. Xyloglucan that had been partially degraded by beta-galactosidase to eliminate 44% of galactose residues formed gels at concentrations of between 1 to 2% w/w at gelation temperatures decreasing over the range 27 to 22 degreesC with increasing concentration. The in vitro release of indomethacin and diltiazem from the enzyme-degraded xyloglucan gels followed root-time kinetics over a period of 5 h at 37 degreesC; the diffusion coefficients increasing with temperature increase between 10 and 37 degreesC. The in vitro release of indomethacin from the gels was significantly more sustained than from commercial suppositories. Measurement of plasma levels of indomethacin after rectal administration to rabbits of the gels and commercial suppositories containing an identical drug concentration indicated a broader absorption peak following administration of the gels, and a longer residence time. There was no significant difference in bioavailability of indomethacin when administered by these two vehicles. Morphological studies of rectal mucosa following a single administration of the gels showed no evidence of tissue damage. The results of this study suggest the potential of the enzyme-degraded xyloglucan gels as vehicles for rectal delivery of drugs.

Administration, Rectal↗
PubMed1983

[Experimental study of an ampicillin suppository (KS-R1) in adults and children].

KS-R1, a new rectal suppository of ampicillin (ABPC) sodium, was compared with oral and parenteral ABPC in terms of absorption and excretion in childish patients and healthy adult male volunteers. In addition, the irritation of KS-R1 to the rectum was studied. 1. Eight healthy adult male volunteers received 250 mg (potency) of KS-R1 rectally and 125 mg of ABPC intravenously in a cross-over study. Then, 4 of them were given intramuscularly 250 mg of ABPC, and 3 of the remaining 4 volunteers were given 250 mg of ABPC orally. The rectal administration of 250 mg of KS-R1 resulted in a mean peak ABPC plasma level (Cmax) of 2.6 mcg/ml at 30 minutes, and then ABPC levels declined with biological half-life (T2/1) of 0.55 hour. The peak time (Tmax) of occurrence after rectal dose of KS-R1 was earlier than that after oral dose of ABPC, and was equal to that after intramuscular dose of ABPC. Cmax after rectal dose of KS-R1 was equal to that after the oral dose, and was about 40% of the value attained with the intramuscular dose. Urinary recovery of ABPC during 6 hours after rectal dose of KS-R1 was 24.0%, compared with 34.0% for the oral dose, 59.6% for the intramuscular dose and 61.4% for the intravenous dose. The relative bioavailability of KS-R1, calculated on the basis of urinary recovery after intravenous administration of ABPC, was about 40%. 2. When KS-R1 (250 mg) was given to 2 adult volunteers 3 times daily for 5 days, no remarkable difference was found in plasma concentration and urinary recovery of ABPC. The pharmacokinetic parameters following the last administration were similar to those following a single administration of KS-R1. 3. KS-R1, oral ABPC and intravenous ABPC were administered at the dose of 125 mg (potency) to 5, 4 and 3 children and at the dose of 250 mg (potency) to 5, 3 and 3 children, respectively. Peak plasma level (Cmax) of ABPC after rectal administration of 125 mg and 250 mg of KS-R1 was reached in 15 minutes, indicating 4.8 and 7.1 mcg/ml, respectively. Peak time (Tmax) of ABPC after the rectal doses of KS-R1 was about 2 hours earlier than that after oral doses of ABPC. Cmax after KS-R1 was 3-4 times as high as that after the oral doses. Area under the curve (AUC) with KS-R1 was 1.38-1.55 times greater than that of oral ABPC, and about 24% of the values obtained with intravenous doses of ABPC. Urinary recoveries of ABPC rectal doses of KS-R1 were 30.4 to 45.6%, compared with 29.2 to 30.8% for the oral doses and 61.1 to 76.1% for the intravenous doses.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1999

In vitro and in vivo evaluation of effects of sodium caprate on enteral peptide absorption and on mucosal morphology.

Sodium salts of medium-chain fatty acids, sodium caprate (C10) in particular, have been used as absorption-enhancing agents to promote transmucosal drug absorption. In this study, we conducted both in vitro and in vivo experiments to investigate the effects of C10 on intestinal permeabilities and mucosal morphology. Mucosal addition of C10 (13-25 mM) reduced the transepithelial electric resistance (TEER) of cultured monolayers of the human intestinal cell line Caco-2 by 40-65% and, upon removal of C10, a marked tendency of TEER recovery was recorded. C10 added mucosally at 13-50 mM increased the transports of mannitol and polyethylene glycol (PEG) 900 across Caco-2 in a dose-dependent manner. In contrast, the transport of a model D-decapeptide was maximally enhanced with 20-25 mM C10. No noticeable morphological alteration of the Caco-2 monolayers was observed after a 1-h mucosal pretreatment with C10. Co-delivery with C10 (0.05-0.5 mmol/kg) into the rat terminal ileum increased the D-decapeptide bioavailability (BA) dose-dependently. With 0.5 mmol/kg C10 co-administered, D-decapeptide percent BA was elevated from 2 to 11%. Following a 1-h incubation with 0.5 mmol/kg C10 (in liquid or powder form) non-invasively delivered into the rectal lumen, no signs of histological change in the rectal mucosa were detected. These results demonstrate that C10 can promote intestinal absorption of a small peptide without causing detrimental alterations of the intestinal mucosa. C10 thus seems to be a good candidate as an enhancing agent for improving the oral BA of small therapeutic peptides.

Animals↗
PubMed1976

Pharmacokinetics and relative bioavailability of vinylbital in man after oral and rectal administration.

A sensitive and specific method for the quantitative determination of 5-vinyl-5-(1-methylbutyl)-barbituric acid (vinylbital) in plasma was developed, by using gas chromatography with alkali flame ionization detection. The method is suitable for measuring vinylbital plasma levels in man after administration of therapeutic doses. The pharmacokinetics and relative bioavailability of vinylbital after oral and rectal administration were studied in man. Tablets (Bykonox) containing 150 mg vinylbital, were used for the oral experiments and suppositories (Suppoptanox, polyethylene glycol base) containing 200 mg vinylbital, were used for rectal administration. Six volunteers participated in a cross-over way in the study. Vinylbital plasma concentrations were determined at regular intervals after drug administration. Absorption and elimination of vinylbital appeared to occur according to a single first-order process and the plasma concentrations were fitted by computer according to the equation intrinsic to the one-compartment open model after oral or rectal administration. The lag time was shorter for the suppository than for the tablet, whereas the absorption rate was faster for the tablet (mean absorption half-life 0.24 h compared with 0.64 h for the suppository). The elimination half-life of vinylbital varied from 17.6 to 33.5 h, with a mean value of 23.5 h for oral administration and 23.8 h for rectal administration. The half-lives were not considerably different on the two occasions for the individual volunteers. The average bioavailability of vinylbital for the suppository, relative to the tablet, was approximately 93%. Three volunteers collected their urine during 3--4 days after administration of a tablet. Unchanged vinylbital was determined and approximately 1.6% of the administered dose was excreted as unchanged drug. Some preliminary experiments of repetive vinylbital administration showed that self-induction of metabolism did not occur.

Administration, Oral↗
PubMed1988

[Perspectives on atypical routes of insulin administration. Oral, rectal, and nasal routes].

The present review concerns the current possibilities of insulin administration through the oral, rectal or nasal routes. The use of vehicle such as liposomes or various polymers protecting the hormone against the digestive enzymes allowed to improve the absorption of insulin after its oral administration. Moreover, the use of various surfactants favours the resorption of insulin through the intestinal, rectal and nasal mucosae. However until now, none of these routes has sufficient reliability and reproducibility to be considered for routine treatment of diabetes mellitus.

Administration, Oral↗