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Objective We aimed to 1) develop physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models of a novel midazolam rectal gel in healthy adults, 2) assess the contribution of different physiologically relevant factors in rectal absorption, and 3) to provide supports for future clinical studies of midazolam rectal gel. Methods We developed the rectal PBPK model after built the intravenous and the oral PBPK model. Then, the physiological progress of rectal route was described in terms of the drug release, the rectal absorption and the particle first-pass elimination. Next, the validated PBPK model was combined with the sigmoid Emax PD model. This PBPK/PD model was used to identify the dose range and the critical parameters to ensure safety sedation. Results Based on the simulations, the recommended maximum dose for adults’ sedation was 15 mg. And the retention time of midazolam rectal gel should be longer than 3 h to reach over 80% pharmacokinetics and pharmacodynamics effects. Conclusion We successfully developed a PBPK/PD model for the midazolam rectal gel, which accurately described the PK/PD behavior in healthy adults and indicated the transit time of rectum was the most sensitive parameter for absorption. This PBPK/PD model would be expected to support the future clinical studies and pediatric application.

Neonatal sepsis is a major cause of infant mortality in developing countries because of delayed injectable treatment, making it urgent to develop noninjectable formulations that can reduce treatment delays in resource-limited settings. Ceftriaxone, available only for injection, needs absorption enhancers to achieve adequate bioavailability via nonparenteral administration. This article presents all available data on the nonparenteral absorption of ceftriaxone in humans and animals, including unpublished work carried out by F. Hoffmann-La Roche (Roche) in the 1980s and new data from preclinical studies with rabbits, and discusses the importance of these data for the development of noninjectable formulations for noninvasive treatment. The combined results indicate that the rectal absorption of ceftriaxone is feasible and likely to lead to a bioavailable formulation that can reduce treatment delays in neonatal sepsis. A bile salt, chenodeoxycholate sodium salt (Na-CDC), used as an absorption enhancer at a 125-mg dose, together with a 500-mg dose of ceftriaxone provided 24% rectal absorption of ceftriaxone and a maximal plasma concentration of 21 µg/ml with good tolerance in human subjects. The rabbit model developed can also be used to screen for the bioavailability of other formulations before assessment in humans.

Objective: The aim of this report is to discuss whether or not rectal levodopa administration is useful in some situations. Background: In situations where oral intake of levodopa formulations is not possible, the treatment options of Parkinson's disease patients are limited. The literature describes no or low rectal absorption of levodopa. Case Description: A patient with an ileus was unable to take oral medication. After consulting the neurologist and pharmacist, the surgeon decided to describe a rectal formulation of levodopa/carbidopa (100/25 mg) once daily. On day 3 of the therapy, 1 h after administration of the rectal formulation of levodopa/carbidopa, a blood sample was drawn. The patient was unable to take his other Parkinson medication; therefore the dose of the rectal levodopa/carbidopa was increased to 5 times a day. Results: Full control of the symptoms was not achieved, but alleviation of the most severe tremor and rigidity was seen, which was confirmed by the neurologist, nurses and patient. The levodopa concentration detected was 17 nmol/l. Compared to levodopa concentrations described in the literature (1,400-12,000 nmol/l), the concentration is very low. There are some possible explanations for the low concentration detected. The presence of a specific amino acid transport system in the rectum is not known, which could lead to no or reduced absorption. The poor rectal absorption of carbidopa leads to a higher conversion of levodopa to dopamine peripherally. Conclusions: In situations where patients are unable to take oral medication, rectal administration of levodopa/carbidopa is worth considering.

The available routes of administration commonly used for medications and fluids in the acute care setting are generally limited to oral, intravenous, or intraosseous routes, but in many patients, particularly in the emergency or critical care settings, these routes are often unavailable or time-consuming to access. A novel device is now available that offers an easy route for administration of medications or fluids via rectal mucosal absorption (also referred to as proctoclysis in the case of fluid administration and subsequent absorption). Although originally intended for the palliative care market, the utility of this device in the emergency setting has recently been described. Specifically, reports of patients being treated for dehydration, alcohol withdrawal, vomiting, fever, myocardial infarction, hyperthyroidism, and cardiac arrest have shown success with administration of a wide variety of medications or fluids (including water, aspirin, lorazepam, ondansetron, acetaminophen, methimazole, and buspirone). Device placement is straightforward, and based on the observation of expected effects from the medication administrations, absorption is rapid. The rapidity of absorption kinetics are further demonstrated in a recent report of the measurement of phenobarbital pharmacokinetics. We describe here the placement and use of this device, and demonstrate methods of pharmacokinetic measurements of medications administered by this method.

This case describes the use of valproic acid suppositories for secondary seizure prophylaxis in a geriatric veteran with a feeding and swallowing disorder. The effectiveness of valproic acid suppositories is outlined to reinforce the need for compounding pharmacies to have this formulation available to meet the needs of geriatric patients.

To investigate the rectal absorption of vigabatrin in rats, based on the hypothesis that PAT1 (Slc36a1) is involved.Male Sprague-Dawley rats were dosed rectally with five different gels, varying in buffer capacity, the amount of vigabatrin, and co-administration of proline or tryptophan. Western blotting was used to detect rPAT1 in rat rectal epithelium. X. Laevis oocytes were injected with SLC36A1 cRNA for the expression of hPAT1, prior to two-electrode voltage clamp measurements.rPAT1 protein was present in rat rectal epithelium. Approximately 7%-9% of a 1 mg/kg vigabatrin dose was absorbed after rectal administration, regardless of the formulation used. Increasing the dose of vigabatrin 10-fold decreased the absolute bioavailability to 4.2%. Co-administration of proline or tryptophan changed the pharmacokinetic profile, indicating a role of PAT1 in the rectal absorption of vigabatrin. Transport of vigabatrin via hPAT1 expressed in X. Laevis oocytes had a K(m) of 5.2 ± 0.6 mM and was almost completely inhibited by tryptophan.Although vigabatrin is a PAT1 substrate and the rPAT1 protein is expressed in the rectum epithelium, vigabatrin has low rectal absorption in rats.

The aim of this work was to improve the rectal bioavailability of quinine hydrochloride by designing thermosensitive and mucoadhesive gels intended for rectal delivery. The rheological and mucoadhesive properties of poloxamer 407 solutions have been modulated by addition of hydroxypropylmethycellulose (HPMC) and propanediol-1,2. In vitro release and rectal absorption of quinine have been highlighted by a dialysis dissolution testing method and by the determination of bioavailability of the different formulations in rabbits. Increasing the proportions of HPMC and poloxamer in the formulations resulted in a prolonged release of quinine. Indeed, compared to the DT 50% of a rectal solution and a simple HPMC gel (27 and 65 min, respectively) the DT 50% of thermosensitive ternary systems was increased and ranged between 80 and 138 min, depending on the system composition. The release rate depended strongly on the elasticity of the gels after thermogelation. The absolute rectal bioavailability of quinine determined in rabbits was significantly improved with these thermosensitive and adhesive systems. It increased from 62% for the rectal solution to 98% for a ternary system 16/0.5/30 (poloxamer (16%)/HPMC (0.5%)/propanediol-1,2 (30%)). As a result of combined bioadhesion and prolonged release of quinine in vivo , higher average values of MRT and t max (9.1 ± 0.2 h and 30 min, respectively) were obtained compared to the rectal solution (6.9 ± 0.9 h and 15 min, respectively). Moreover, these formulations presented a very good rectal tolerance. Modulation by HPMC of the viscoelastic and mucoadhesive properties of poloxamer 407 thermogelling solutions allowed a prolonged release of quinine hydrochloride and an improvement of bioavailability in rabbit.

Alendronate sodium (ALD) is a bisphosphonate medication used in the treatment and prevention of osteoporosis. Absorption of ALD as oral formulation is very poor (0.5%-1%). Its bioavailability can decrease with food effect. It has some gastrointestinal adverse effects such as gastritis, gastric ulcer, and esophagitis. The aim of this study was to develop a rectal formulation of ALD as an alternative to oral route and to investigate the absorption of it by using gamma scintigraphy. For this reason, ALD was labeled with Technetium-99m ((99m)Tc) by direct method. The radiochemical characterization of the (99m)Tc-ALD was carried out by paper chromatography, thin layer chromatography, and electrophoresis methods. The labeling efficiency of (99m)Tc-ALD was found 99% without significant changes until 6 h postlabeling at room temperature. The rectal suppositories containing (99m)Tc-ALD were prepared by fusion method using polyethylene glycol (PEG) 1500. The (99m)Tc-labeled ALD suppositories were administrated to rabbits by rectal route. Serial scintigrams over all bodies of the rabbits were obtained at different time intervals using a gamma camera. We found that the rectal absorption of (99m)Tc-ALD from suppository formulation was possible. According to our results, this formulation of ALD can be suggested for the therapy of osteoporosis as an alternative route.

We previously reported that the fatty base suppository containing sodium laurate (C12) and taurine (Tau) (C12-Tau suppository) could enhance the colonic absorption of rebamipide, a poorly water-soluble and poorly absorbable drug, without any serious mucosal damages in rats. In the preset study, in order to make C12-Tau suppositories available for practical use, the scaling-up studies of animal and formulation size were performed, compared with the suppositories containing sodium caprate (C10) (C10 suppository) at the same amounts as those contained in the commercial products. Twenty-mg C12 improved the dissolution of rebamipide from suppository remarkably and the addition of 30-mg Tau only slightly decreased the dissolution rate. The absorption of rebamipide from rabbit rectum was more markedly improved by suppositories containing C12 than C10 suppositories. Although Tau tended to attenuate the absorption-enhancing effect of C12, several C12-Tau suppositories kept high bioavailability values, which were much higher than control. Histopathological studies showed that Tau exerted the cytoprotective action and that C12-Tau suppositories were better than C10 suppositories in safety. Considering the balance between efficacy and safety, the suppository containing 10- or 20-mg C12 with 30-mg Tau is better than C10 suppositories as commercial products and could be promising for practical use in human.

The aim of this in-vivo perfusion study in humans was to investigate the influence of a penetration enhancer, sodium caprate, on the rectal absorption of phenoxymethylpenicillin and antipyrine. Six subjects, 3 male and 3 female, were included in two separate studies using perfusion solution of different pH (T1 and T2, respectively). Each in-vivo rectal perfusion investigation lasted for 200 min and consisted of two periods of 100 min, the first serving as a control, and sodium caprate being added in the second period in both T1 and T2. The concentrations of phenoxymethylpenicillin, antipyrine and sodium caprate in the outlet perfusate were assayed by HPLC, as was the plasma concentrations of phenoxymethylpenicillin. At pH 6.0 (0–100 min) the fraction absorbed (fabs) and effective permeability (Peff) of phenoxymethylpenicillin were 0.3% and 0.06 × 10−4cms−1, respectively, and remained unaffected by the addition of sodium caprate. When the same subjects were perfused at pH 7.4, the fabs and Peff of phenoxymethylpenicillin were 2.4% and 0.11 times 10−4cms−1 (0–100 min), respectively, also remaining unchanged by addition of sodium caprate (100–200 min). It was possible to determine the plasma AUC of phenoxymethylpenicillin after addition of sodium caprate in three subjects at both pHs; this was in the range of 14.0–62.8 and 56.4–231 (min μ mol L−1) at pH 6.0 and 7.4, respectively. Interestingly, there was a correlation between Peff for sodium caprate and the individual plasma AUC and Cmax of phenoxymethylpenicillin, which indicates that the permeability of the enhancer in the tissue upon which it should act is crucial for achieving an effect. The fabs and the Peff of antipyrine were not affected at either pH when sodium caprate was added to the perfusion solution. In conclusion, the plasma pharmacokinetics of phenoxymethylpenicillin suggested a slightly increased rectal absorption at pH 7.4 in subjects where sodium caprate was transported into the rectal tissue. However, the increased Peff for phenoxymethylpenicillin was too small to detect from the outlet perfusate, which suggests that sodium caprate alone has a limited effect on the permeability in-vivo across the rectal epithelium when it is presented in a solution.

A self-emulsifying system (SES), a mixture of an oil and a surfactant which forms an oil-in-water emulsion, is expected to improve the in vitro drug dissolution and enhance the in vivo drug absorption. In this study, a poorly water-soluble drug, indomethacin (IDM) was incorporated into the SES to increase bioavailability. The SES with 30% of Tween 85 and 70% of ethyl oleate, EO (w/w) was selected as an optimized formulation (high drug loading, low surfactant concentration, and small particle size). After an oral administration of the SES containing IDM and IDM suspension, (IDM was suspended in methyl cellulose), 22.5 mg/kg as IDM, to rats, the area under the plasma concentration-time curve from time zero to the last measured time in plasma, 12 h (AUC(0-12 h)) was significantly greater (57% increase) in the SES, suggesting that oral absorption of IDM increased significantly by the SES. After a rectal administration of gelatin hollow type suppositories, filled with the SES containing IDM and IDM powder physically mixed with the SES, 22. 5 mg/kg, to rats, the AUC(0-12 h) also increased significantly (41% increase) by the SES, suggesting that rectal absorption of IDM also increased significantly by the SES.

Carvedilol, a nonselective β-blocking agent, has been widely used in the treatment of hypertension, and angina pectoris. It is subject to an extensive hepatic first-pass metabolism following oral administration, with a reported systemic bioavailability of between 22 and 24%. Since it is commercially available only in tablet form, the rectum is an effective administration method for elderly patients and for whom it is difficult to swallow tablets. For this reason the rectal absorption of carvedilol was studied in rats.The plasma carvedilol levels were found to be significantly higher than the oral administration levels at 15 min, 1, 4, 6, 8, 12 and 24 hr after the rectal administration of 20 mg/kg carvedilol. In addition, the drug pharmacokinetic parameters, comprising maximum plasma concentration (Cmax) was 1.7 times higher, and area under the concentration-time curve up to 24 hours (AUC0-24) was 2.2 times higher after rectal administration. In comparison to the AUC0-24 values, the relative bioavailability of carvedilol after oral administration was 19.3% and also after rectal administration was 42.2%.These results are thought to be caused by a reduced first-pass metabolism, and the rectum was thus conformed to be an effective administration route for calvedilol.

(1998). Improvement of Nalbuphine Bioavailability Through Rectal Administration of a Prodrug. Pharmaceutical Development and Technology: Vol. 3, No. 1, pp. 131-134.

The pharmacokinetics of nalbuphine (0.3 mg/kg) administered by the rectal route were studied in ten children undergoing general anaesthesia for minor surgery. Blood sampling was carried out for 8 h after rectal administration and plasma drug concentrations were measured by high performance liquid chromatography using electrochemical detection after an optimized solid-phase extraction procedure. The mean time to achieve the maximum plasma concentration (Cmax = 24 +/- 15 ng/mL) was 25 +/- 11 min and the elimination half-life was 2.7 +/- 0.7 h. The coefficients of variation for Cmax and the concentration-time curve (AUC) were 62 and 68%, respectively. Although rectal absorption is considered irregular, the large intersubject variability is also explainable by a variable hepatic bypass for a drug, like nalbuphine, that undergoes extensive first-pass metabolism. No problem of analgesic efficacy or of local tolerance was reported. In conclusion, the rectal route of administration provides a rapid and reliable absorption of nalbuphine.

Rectal gels prepared with water-soluble dietary fibers, xanthan gum and locust bean gum, were evaluated as a vehicle for the rectal administration of buprenorphine hydrochloride (BN-HCI) in rabbits. The maximum plasma concentration of buprenorphine (BN) gradually decreased with increase in the gum concentration. The values of the mean residence time (MRT0–2) increased in proportion to increasing gum concentration. The absorption of BN from rectal gels containing 0.5, 1 and 2% (w/ v) gum compared with those based upon polyethylene glycol (PEG), was more rapid. In particular, the absorption of BN from rectal gels containing 1% (w/v) gum was extremely fast without decreasing the areas under the plasma concentration vs. time curves (AUC0–2). The bioavailabilities obtained in rabbits correlated well with the in vitro release rates determined using dialysis tubing. A histopathological study revealed severe mucosal hyperemia, which was thought to be the main characteristic of rectal irritation induced by PEG-base suppositories. These results suggested that BN-HC1 rectal gels prepared with xanthan gum and locust bean gum were practical rectal preparations with rapid absorption and reduced side effects.

Pharmacokinetics of morphine and its glucuronides in plasma were studied after rectal administration of hollow-type oleaginous suppositories containing kneading mixtures of morphine hydrochloride, alpha-cyclodextrin, and/or xanthan gum in rabbits. In combination with xanthan gum, alpha-cyclodextrin reduced the first-pass metabolism of morphine in the rectal mucosa and by the liver and improved the apparent rectal bioavailability of the opioid about 4 fold. In vitro permeation studies using an isolated rectal mucosal preparation of rabbits revealed that alpha-cyclodextrin increased the transepithelial conductance and facilitated the transport of morphine through the rectal mucosa. Furthermore, alpha-cyclodextrin facilitated its own mucosal permeation and reduced the glucuronidation of morphine during the passage through the rectal mucosa, probably through restricting the formation of a catalytic complex of morphine with glucuronyltransferases, rather than because of the enzyme saturation. The present data suggest that alpha-cyclodextrin in combination with xanthan gum is particularly effective in improving the rectal bioavailability of morphine from hollow-type suppositories.

Rectal absorption of omeprazole, a proton pump inhibitor, from suppositories was studied in rabbits. The suppositories were prepared by the conventional melting method with two types of bases, water-soluble polyethylene glycol (PEG) 4000 and oil-soluble Witepsol H15 bases, and administered intrarectally (ir) to rabbits at a dose of 10 mg omeprazole/kg. The plasma omeprazole concentration-time profiles of the two suppositories were compared with those following intravenous (iv) administration of the same dose. There were no significant differences between the two suppositories in bioavailabilities and peak plasma concentrations (Cmax). Bioavailabilities and Cmax of PEG- and Witepsol suppositories were 30.3 and 33.9%, and 7.0 and 5.6 μg/ml, respectively. However, PEG suppository showed significantly (P

Omeprazole is a gastric proton pump inhibitor. Since it is commercially available only as an enteric-coated tablet, it is inappropriate for administration to patients for whom it is difficult to swallow tablets or whose intestinal absorption is poor due to gastrointestinal failure. As the rectum is an effective route for the administration for various compounds, the rectal absorption of omeprazole from a suppository containing an omeprazole tablet was studied in healthy male volunteers. The pharmacokinetic parameters were compared with the published data after oral dosing, revealing that the AUCs of omeprazole administered rectally and orally were similar. The rectum was thus conformed to be an effective administration route for omeprazole and the suppository containing an omeprazole tablet to be a practical preparation because it can be prepared rapidly to comprise an accurate drug dosage.

The effect of the viscosity of sodium hyaluronate solution on the rectal absorption of morphine was determined in rabbits. Hollow-type suppositories containing 10 mg morphine in viscous sodium hyaluronate solution of various mean molecular weights (MWs) were prepared. Rectal absorption of morphine in the sodium hyaluronate solution (MW 2.1 x 10(6) daltons) was dependent on sodium hyaluronate concentrations in the range of 0.1 to 3% (w/v). Bioavailability after rectal administration of morphine in 0.1% sodium hyaluronate solution is consistent with that of morphine solution in the absence of sodium hyaluronate and the sustained-release plasma profile was observed for morphine in 3% sodium hyaluronate solution. Administration of hollow-type suppositories containing 10 mg morphine in 1% sodium hyaluronate solution resulted in the highest bioavailability of approximately 2-fold that after administration of morphine in physiological saline solution. Five kinds of sodium hyaluronate solution with MWs of 2.4 x 10(5), 1.0 x 10(6), 1.8 x 10(6) and 2.1 x 10(6) daltons and respective viscosities of 70, 3.3 x 10(3), 3.2 x 10(6), 5.1 x 10(3) and 5.7 x 10(3) cP (20 degrees C) were examined. Optimal viscosity of the sodium hyaluronate solution was found to enhance rectal morphine absorption. These results indicate that the selection of relevant viscosity of the sodium hyaluronate solution may contribute to the improvement of bioavailability of morphine on rectal administration.

ウシにおけるアンピシリン(以下ABPC)坐剤の直腸からの吸収性について体重411～639kgの成牛24頭を用い検討した.実験群はI群(対照群)にはウシに対する一般的投与量であるアンピシリンナトリウム(以下ABPC Na) 10mg/kgずつを筋肉内注射,II群には吸収促進剤無添加ABPC坐剤をABPC Naとして20mg/kgずつを直腸内投与,III群には吸収促進剤としてカプリン酸ナトリウム10W/W%添加した坐剤をABPC Naとして20mg/kgずつを直腸内投与し,投与後の薬物動態および副作用の発現について比較検討した.血清濃度の最高値は,I群では投与後30分で12.83±4.51μg/ml,II群では30分で2.43±1.48μg/ml, III群では45分で8.83±3.70μg/mlを示した.最高濃度(Cmax)および最高濃度発現時間(Tmax)は,I群13.96±3.61μg/ml,0.72±0.20時間,II群2.80±1.25μg/ml,0.66±0.21時間,III群9.63±4.56μg/ml, 0.78±0.15時間であった.吸収促進剤を添加することにより,ABPC坐剤の直腸からの吸収性が約3.5倍増加することが明らかとなり,また筋肉内注射群のおよそ2/3に相当する血清濃度が得られれた.この値は一般的病原菌の最小発育阻止濃度を十分に上回るものであった.また,坐剤による副作用と考えられる症状はII, III群いずれにも認められなかった.これらの成績より,ウシの細菌性感染症に対してABPC坐剤の直腸内投与は,安全かつ有効な治療方法であることが示唆された.

Oxaprozin (OXP) suppositories were prepared and their characteristics were investigated. In vivo rectal absorption studies were carried out in rats by measuring the plasma concentrations of OXP. The amorphous state of OXP with polyvinylpyrrolidone (PVP) was obtained using the dissolving method, and the effect of this solid dispersion on the dissolution of OXP was determined. Enhanced rectal absorption of OXP in the amorphous state was not observed in the OXP-PVP solid dispersion system. By using the pH controlled method, a 6-fold effective increase in Cmax was obtained. The increased bioavailability of OXP resulted in a modification of the dissolution characteristics of OXP by an internal buffer system with Na2HPO4.

We designed a preparation containing both a drug and an adsorbent as a controlled-release system and selected aminophylline as a model drug for use in this study.The preparation consisted of two components: to adsorption equilibrium existing between the drug adsorbed onto an adsorbent and free drug, and diffusion of free drug into blood capillaries via the rectal mucosae. Because of the interlocking of the two components, a continuous supply of the drug via desorption corresponding to the elimination of the drug from the blood circulation was confirmed to be possible, which resulted in maintaining a constant plasma level over a long period following rectal administration.The in vitro release study showed that an optimal adsorbent for the preparation was activated charcoal, especially JP XI grade, and that the most adequate from for rectal administration was by enema. In the in vivo rectal absorption study using rabbits, the preparation provided by an enema enhanced the mean residence time (MRT) of aminophylline by 1.7-fold in comparison with aminophylline solution, and indicated a constant plasma level of theophylline over 6 hours.

The bioavailability of morphine after rectal administration using three types of suppositories containing morphine hydrochloride (10 mg) in different added forms was evaluated in rabbits. Three types of suppositories were constructed with a base material (Witepsol H-15): a conventional suppository containing morphine hydrochloride mixed with a base material, a hollow-type suppository containing morphine in an aqueous solution in its cavity, and a hollow-type suppository containing morphine as a powder (hydrochloride salt) in its cavity. The plasma concentrations of morphine and its metabolites, morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G), were determined. The mean AUC0-6 of morphine after rectal administration of the hollow-type suppository containing powdered morphine was significantly higher than that after the administration of a conventional suppository, whereas the mean AUC0-6 of M-3-G was lower than that after administration of a conventional suppository. The mean AUC0-6 of M-6-G by a hollow-type suppository containing powdered morphine was higher than that by a conventional suppository. Although the mean AUC0-6 ratio of M-3-G to morphine after administration of a conventional suppository was three times larger than that of a hollow-type suppository containing powdered morphine, the mean AUC0-6 ratios of M-6-G to morphine after use of the three types of suppositories were all approximately 1.0. This study demonstrates that the hollow-type suppository containing powdered morphine is a more effective rectal dosage vehicle than the conventional suppository.

The in vitro release of bumetanide from macrogol suppositories with and without weak acids (citric acid and tartaric acid) was studied. The release of bumetanide was not affected when weak acids were added to the suppositories. The in vivo rectal absorption of bumetanide from the suppositories was evaluated in rabbits. The bioavailability (absolute), expressed as the ratio of the area under the plasma concentration-time curve (AUC) following oral administration of bumetanide, was 39% that of intravenous administration. The value in bumetanide following rectal administration of the suppositories without weak acids was 32%. Each absolute bioavailability following rectal administration of the suppositories with 5% citric acid and 5% tartaric acid was 52% and 42%, respectively. These values were significantly larger than those of rectal administration of the suppositories without weak acids. Particularly, the bioavailability following rectal administration of the suppositories containing citric acid was significantly different from even those of oral administration. The absorption rate constants of bumetanide from the suppositories with weak acids were significantly larger than those following oral administration. These results indicated the possibilities of the rectal route of administration of drugs which are weak organic acids and show low or variable bioavailability following oral administration.

Drug informations on a suitable insertion duration of suppositories and on a deal with the problem of the loss from rectal are essential for the proper therapy of patients. In the present study, we collected the data on drug disposition after administration of commercially available suppositories which had systemic pharmacological effects, and then analized pharmacokinetically on the problems of the insertion duration of them and the loss from rectal. The rectal absorption rate and the cumulative absorption ratio of drugs from commercially available suppositories were estimated by the deconvolution analysis. The plasma concentration data after rectal and intravenous administration were obtained in nine kinds of drugs, which were ampicilline, ketoprophene, indomethacine, acetoaminophene, phenobarbital, donperidone, bromazepam, buprenorphine and morphine. It was shown that the completion time of the absorption of drug from the suppositories varied largely from 50 min for ampicilline to 8 hours for donperidone. Comparing the time periods required to reach to 50% in the cumulative absorption ratio in those drugs, the fastest time was found in ampicilline (15 min), and the slowest was in aminophylline (90 min). These findings make it possible to the persue counseling for the patients on the proper insertion duration of each suppositories. The simulation of the time course of blood drug concentration after the loss of suppositories from rectal and the supplement of them was successfully performed, suggesting that the optimal drug concentration could be controled by the rational supplemental dose. In conclusion, the drug information based on the deconvolution analysis can be useful to instruct a rational use of suppositories to the pharmacist and/ or the patients.

The effect of polysorbate 80 on the rectal absorption of carbamazepine from a fatty suppository was investigated in the rabbit. Each animal received successively (with a wash-out of 1 week between every administration) two oral capsules of 100 mg, a suppository of carbamazepine 200 mg without surfactant, and a suppository of carbamazepine 200 mg including 2% polysorbate 80. After oral administration, the following values were obtained: C max 43 ± 17 μ mol/l; T max , 5.1 ± 2.3 h; AUC, 391 ± 204 μ mol h l −1 . Subsequent to rectal administration of a suppository without polysorbate 80, the corresponding values were: C max , 28 ± 2.9 μ mol/l; T max , 2.8 ± 1.3 h; AUC, 203 ± 29 μ mol h l −1 . The inclusion of polysorbate 80 resulted in a C max of 26 ± 6.2 μ mol/l at 1.7 ± 0.5 h. The AUC value amounted to 242 ± 66 μ mol h l −1 . In the rabbit, rectal administration of carbamazepine from a suppository is more regular than oral absorption from capsules. Polysorbate 80 could enhance the rate and reproducibility of rectal absorption of carbamazepine from a fatty suppository: the serum concentration at 45 min amounted to 20.9 ± 3.8 μ mol/l for the suppository containing polysorbate 80 vs 14.6 ± 5.9 μ mol/l for that without.

Rectal absorption of Zidovudine (3′-azido-3′-deoxythymidine, AZT) was investigated in order to determine the feasibility of developing AZT suppositories. Although the small intestine shows a higher absorption rate than the stomach and large intestine in rats, considerable absorption of AZT was observed from the lower large intestine (8 cm above the anus). A sustained-release suppository was prepared by direct compression of hydroxypropyl cellulose (HPC) with AZT. During in vivo experiments in rats, this suppository (10 mg or 37.5 μmol AZT/kg) maintained constant plasma levels above 1 μM for more than 6 h. The results suggest that suppositories can prove useful as an alternative dosage form of AZT administration.

Various suppositories containing phenytoin and phenytoin sodium were formulated with different polyethylene glycol combinations. The three formulae that had the best in vitro release rate were administered to rabbits. Phenytoin was well absorbed from the suppositories, and the results show that rectal administration of phenytoin can be an alternative to oral administration.

Various N-substituted [(3- or 4-aminomethyl)benzoyloxymethyl]allopurinol derivatives were synthesized by esterification of 1-(hydroxymethyl)allopurinol and evaluated as water-soluble prodrugs with the aim of developing preparations suitable for parenteral and/or rectal administration. The derivatives combine a good solubility and high chemical stability in weakly acidic solutions with a high susceptibility to undergo enzymatic hydrolysis in plasma. The derivatives were much more lipophilic than allopurinol as determined by partition experiments in octanol-aqueous buffer solution. The rectal and parenteral absorption characteristics of three derivatives and of allopurinol were assessed in rabbits. Following intravenous administration the derivatives were quickly converted yielding allopurinol in quantitative amounts. After rectal administration of the three prodrugs an absolute bioavailability of 19, 38 and 41%, respectively, was found whereas the rectal absorption of allopurinol itself was only 3%.

There are various reasons for rectal drug administration. Two of the most obvious ones are situations when patients are vomiting or suffering from nausea, while it has also been shown that it is possible to avoid at least partially hepatic first-pass elimination following rectal administration. An additional reason is the fact that the rectum environment is quite constant with respect to pH; composition, volume and viscosity of fluid; and less influenced by food. This offers the opportunity for rate controlled rectal drug delivery. Indeed it has been shown for various drugs e.g. antipyrine, theophylline, midazolam, lidocaine, nifedipine etc., that rate-controlled rectal drug administration is well possible. For hydrophilic drugs the rectal mucosa acts as a physical barrier and absorption enhancers can be applied to increase the extent and rate of absorption. Various enhancers can be used, NSAID's, bile salts, surfactants, STDHF, fatty acids, mono-, di- and triglycerides, enamines, mixed micelles etc., their mechanisms of action mostly being not fully elucidated, to increase trans- and/or paracellular transport of drug. Increased absorption of drugs has been demonstrated depending also on the rate of administration. In addition, increased absorption of peptides e.g. DEyE and DGAVP and proteins such as insulin, albumin, somostatin analogue, has been accomplished. However, one of the major concerns, tissue and/or membrane damage, especially following repeated application, has not been dealt with satisfactorily. Detailed information about mechanisms of absorption enhancement and of membrane or tissue damage is needed to optimize drug absorption enhancement and reduce damage to at least acceptable levels. For hydrophylic drugs, especially peptides and proteins, the rectal mucosa acts not only as a physical barrier but also as a metabolic barrier. Therefore to increase the extent of absorption of these drugs absorption enhancers and metabolic inhibitors should be applied. This on its turn stresses the need of a careful tuning of the administration of enhancer, inhibitor and drug to obtain the optimum rate and extent of absorption.

Acetaminophen is frequently administered to infants and children for its antipyretic and analgesic properties. Oral administration is the route of choice in daily practice. In some circumstances this is impractical. Rectal administration of acetaminophen is an alternative route. This study measures plasma concentrations following rectal administration of acetaminophen 20 mg.kg-1 (10% Infants' Tylenol Drops, McNeil Consumer Product Co., diluted with an equal volume of sterile water) in five preterm neonates. Serial arterial blood samples were obtained at 0, 15, 30, 60, 120, and 240 min. Pharmacokinetic parameters were (mean +/- SD): Cmax (maximum plasma concentration) of 8.38 +/- 3.92 micrograms.ml-1 and Tmax (time to reach maximum plasma concentration) of 78.0 +/- 40.2 min. Our results show that 20 mg.kg-1 of acetaminophen rectally results in low plasma levels in preterm neonates.

The rectal route of antibiotic administration might be used effectively when other routes of administration are inadequate or unsuitable. With the use of various adjuvants, the rectal route can provide satisfactory pharmacokinetics and acceptable local tolerance. Experiments in animals have demonstrated the influence of the pharmaceutical formulation of suppositories on the rectal absorption and systemic distribution of beta-lactams and aminoglycosides. In healthy volunteers and in children under treatment, similar adjuvants--mainly glyceride mixtures or non-ionic surface agents--have increased the rectal absorption of aminopenicillins, cephalosporins and macrolides. Other antibiotics, including metronidazole and cotrimoxazole, have been investigated in respect of their potential rectal administration.

OBJECTIVE: To test the hypothesis that rectally administered phenytoin is absorbed in healthy volunteers. DESIGN: This single-center, open-label crossover pilot study compared rectal absorption with intravenous administration of phenytoin injectable solution (7 mg/kg) in healthy volunteers. Twelve serial blood samples were taken from each volunteer beginning at time zero until 36 hours following administration. These were analyzed for presence of phenytoin by immunoassay. SETTING: The study took place at St. Paul's Hospital, a tertiary care center. PARTICIPANTS: Funding permitted for a sample size of five healthy participants, two men and three women, aged 21–45 years. Selection was by volunteer sample. Inclusion criteria were as follows: no known medical conditions, not receiving medication, no history of adverse drug reactions or allergies, not known to be pregnant, and normal liver function as determined per study protocol. MAIN OUTCOME MEASURES: Signs of absorption as indicated by presence of phenytoin in blood samples, maximum concentrations (Cmax), time to Cmax (tmax), AUC, and apparent bioavailability. RESULTS: Maximum mean concentrations of 2.4 ± 1.1 mg/L (mean ± SD) following rectal administration and 11.2 ± 1.6 mg/L following intravenous administration were achieved during the first one to two hours (tmax in both treatment arms). Mean apparent bioavailability of the rectally administered phenytoin was 24.4 ± 13.4% (15.8–44.1%). CONCLUSIONS: Results from this pilot study demonstrate that rectal absorption of phenytoin begins within 30 minutes following single-dose administration and was reported by four out of five volunteers to be the preferred route. Further studies are required before extrapolation can be made to the patient population.

The influence of the hydrophilicity of three suppository bases on the rectal absorption of ketoprofen was studied. Absorption characteristics of ketoprofen were compared after intravenous, oral, and rectal administrations of 100 mg of drug given in a crossover design to five dogs. Rectal formulations included an aqueous solution and three suppository formulations. After oral dosing, ketoprofen was rapidly absorbed (time of maximum concentration, tmax: 0.83 +/- 0.61 h), and a comparison with the intravenous solution indicated a complete bioavailability of 0.90 +/- 0.10. After rectal administration, the rate of absorption, as evaluated with tmax and mean absorption time, was always slower than after oral dosing. A high variability was observed in the plasma concentrations obtained with suppository formulations; bioavailability values were approximately 20% lower than those from the oral solutions. No statistical difference in bioavailability and peak concentrations between the three suppository formulations was observed. Time of peak concentrations, mean absorption times, and fractions of the dose absorbed 6 h post administration did not show a difference in rate of ketoprofen absorption from the three suppository formulations. This study did not reveal a relationship between rate and extent of ketoprofen rectal absorption and the hydrophilicity of the suppository bases tested.

In this study, we developed a new hollow-type suppository containing elcatonin ((Asu1, 7)-eel calcitonin, ECT), a synthetic derivative of eel calcitonin, which produces hypocalcemia, as a pharmaceutical preparation for self administration, to be used instead of parenteral injections for patients with osteoporosis. The absorption of ECT from the rectal mucous membrane was evaluated by observation of the decrease in serum calcium (Ca) concentrations following rectal administration in rabbits. ECT was efficiently absorbed from the rectum and effectively decreased serum Ca concentrations. The data of the area under the percent decrease in serum Ca concentration (ΔCa%)-time curve (ΔCa%-AUC), assumed to be an index of the pharmacodynamics (pharmacological effect) of ECT, indicated that similar hypocalcemic effects were obtained following rectal and intravenous administrations of ECT. In regard to the effect of coadministration of other compounds on rectal absorption of ECT, no significant difference in the ΔCa%-AUC between rectal ECT administration with or without nafamostat mesilate (a protease inhibitor) was observed. However, the coadministration of ECT with cytochalasin B or monensin (endocytosis inhibitors) significantly decreased the ΔCa%-AUC, indicating that rectal ECT absorption is probably inhibited by endocytosis inhibitors by endocytosis inhibitors. On the other hand, it was found that sodium decanoate, a mediumchain fatty acid (sodium salt), significantly enhanced the rectal absorption of ECT. We conclude that this ECT hollow-type suppository offers promise as a new method for the administartion of ECT.

The oral absorption of omeprazole is incomplete, in part due to first-pass metabolism. We investigated the feasibility of rectal administration of omeprazole by comparing its absorption from a Witepsol H15-based rectal suppository and an orally administered commercial gelatin capsule in 10 male volunteers. Profiles of plasma concentration between two preparations (20 mg) were not statistically different, indicating that the rate and the extent of absorption were similar. Paired t-test revealed no significant differences in area under the curve, mean residence time, and time to peak concentration between two preparations. On the other hand, lag time of absorption and peak concentration were statistically different (p < 0.05) between these preparations. Under these experimental conditions, the rectal route did not produce an improvement in the extent of absorption over an oral capsule.

An attempt was made to optimize the rectal delivery of morphine, using cyclodextrins as an absorption enhancer and polysaccharides as a swelling hydrogel in Witepsol H-15 hollow-type suppositories, and this was tested in rabbits. alpha- and beta-cyclodextrins enhanced the rate and extent of bioavailability, the former being more effective; gamma-cyclodextrin decreased the absorption of morphine. The in-vitro membrane permeation studies using excised rectal sacs revealed that alpha-cyclodextrin enhanced the permeation of morphine through the rectal membranes. In contrast, viscous polysaccharides such as xanthan gum retarded the plasma morphine levels after the rectal administration, reflecting in-vitro slow release characteristics. A combination of alpha-cyclodextrin and xanthan gum produced sustained plasma profiles of morphine along with an increased rectal bioavailability (more than 4 times). From the observation of the distribution behavior of suppositories in rabbit rectum and colon after the rectal administration, xanthan gum was found to prevent the upward spread of the drug. Gross and microscopic observations suggested that this preparation was less irritating to the rectal mucosa.

The suppositories of rifampicin (RFP) containing sodium para-aminosalicylate dihydrate (PAS-Na) were prepared in order to enhance the rectal absorption of RFP. By the addition of PAS-Na, the in vitro release of RFP from the suppositories was enhanced and the hardness of the suppositories decreased. The rectal absorption of RFP from the suppositories containing no PAS-Na (control suppositories) was significantly lower compared to oral administration of it (26%) in human subjects. When PAS-Na was added to the suppository (300 mg), both the area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) increased significantly compared to those of the control suppositories. The rectal absorption of PAS-Na itself from the suppositories seemed to be fast. PAS-Na might increase the absorption of RFP dissolved in the rectal fluid from the suppositories, but not affect the undissolved RFP.

Sustained-release hydrogel suppositories prepared with water-soluble dietary fibers, xanthan gum and locust bean gum, were evaluated as a vehicle for rectal administration of indomethacin (IMC) in rabbits. The drug plasma levels were compared with those after rectal administration of commercial suppositories. When the commercial suppositories were given to rabbits, the plasma concentration reached the maximum level at 30 min after administration followed by a quick reduction, while no sharp peak of plasma levels was seen with the hydrogel suppositories. In particular, the plasma levels observed with the hydrogel suppositories of 1% (w/v) gum concentration were sustained much longer than those after dosing with the commercial suppositories; the mean residence times had higher values without a decrease in the area under the plasma concentration vs. time curves. Histopathological study showed good biological safety of the hydrogel suppositories to the rectal mucosa. These results suggested that the IMC hydrogel suppositories prepared with xanthan gum and locust bean gum were a practical rectal preparation with prolonged action and reduced side effects.

To develop a new treatment for patients with anaemia in which erythropoietin (EPO) can be given without injection, the effects of promoters of the rectal absorption of EPO were studied. Recombinant human (rHu) EPO (5000 units) in a dosing solution or in a rectal suppository was placed in the rectum of healthy rats and changes in serum EPO levels were monitored by an enzyme-linked immunosorbent assay. Without a promoter, rHuEPO was not absorbed. Sodium glycocholate, sodium caprate, and sodium salicylate in the solution of rHuEPO increased the absorption of rHuEPO. Sodium salicylate or sodium caprate in the suppository with rHuEPO also increased its absorption. The bioavailability of rHuEPO in a suppository containing 5% sodium salicylate compared with that by an intravenous injection was 1·2%. rHuEPO given in rectal suppositories containing sodium salicylate and inserted once a day for 6 consecutive days increased erythropoiesis in peripheral blood.

Physicians regularly challenge the hospital pharmacy departments to find alternative routes for the administration of drugs, which can't be withhold, e.g. anti-epileptic drugs. In our hospital we were confronted with the question whether it was possible to administer oxcarbazepine rectally. In the present report data on the absorption of rectally administered oxcarbazepine is presented. No therapeutic bloodlevels were attained after rectal administration. Administration via the oral route, however, gave within the same period of time a therapeutic bloodlevel. It is concluded that the absorption after rectal administration of oxcarbazepine at least in this dose and frequency used is too low to justify application in practice.

An improvement of the rectal absorption of uracil was examined by the application of absorption enhancers in addition to the increased solubility of uracil. Uracil was ground with additives such as MgO, sodium 2,6-dihydroxybenzoate, human serum albumin or hydroxypropylmethylcellulose acetate succinate. Aqueous, oily and powdery formulations, which consisted of the ground mixtures, nicotinamide, urea and absorption enhancers such as polyoxyethylene (23) cetylether (BC-23) or sodium caprate, were prepared. Uracil solubility in the aqueous formulations was increased about 4-13 times that in the corresponding control formulations. When rectally administered to beagle dogs, marked increases in the plasma uracil level were observed in some of the cases of aqueous and oily formulations. In the powdery formulations and formulations containing macromolecular additives, however, absorption improvements was not observed. The results indicated that an improvement in the absorption of uracil was caused by the combinative improving effect of the increased uracil solubility and the promoting effect of absorption enhancers.

The influence of the hydrophilicity of fatty suppository bases on the rectal absorption of the lipophilic drug carprofen (octanol-buffer, pH 7.4; partition coefficient, 40) was investigated in dogs. Five animals received each of six carprofen formulations in a random sequence: intravenous, oral, and rectal solutions, and three suppository formulations. The suppository vehicles tested were semisynthetic glycerides containing saturated fatty acids mainly in the range of C10 to C18 [Massa Estarinum A (MEA), Massa Estarinum B (MEB), and Massa Estarinum 299 (ME299)]; their hydroxyl values increased from 1 for ME299, through 24 for MEB, to 45 for MEA. Following every drug administration, blood samples were collected over a period of 104 h and carprofen plasma concentrations were measured by a specific HPLC method with UV detection. The rate and extent of carprofen absorption were characterized by evaluation of the maximum plasma concentrations (Cmax), the time of their occurrence (tmax), absolute bioavailabilities, statistical moments, and by deconvolution. Carprofen was rapidly and completely absorbed from the oral solution. The maximum concentrations obtained with oral solutions were significantly higher than those observed with rectal solutions and with the three suppository formulations. Results obtained with the rectal solution exhibited a high degree of intersubject variability. After rectal administration of suppositories, the rate and extent of carprofen absorption increased with the hydroxyl value of the suppository base; the mean absorption times (MAT) and tmax were shorter with MEA (2.15 and 1.7 h, respectively) than with the less hydrophilic vehicles (MEB: 4.09 and 2.1 h, respectively; ME299: 4.22 and 2.4 h, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

A case of recurrent respiratory depression due to rectal absorption of concealed opiate drugs in an intravenous drug abuser held in police custody is described. The importance of rectal examination in intravenous drug abusers in police custody is stressed and it is emphasised that drugs may have been concealed in a body cavity at the time of arrest. The use of both the intramuscular and intravenous route for the administration of naloxone in treatment of unconscious intravenous drug abusers suspected of having overdosed on opiates is advocated as these patients frequently discharge themselves from hospital on regaining consciousness and may later present with recurrent respiratory depression.

The rat enteral and rabbit rectal models were utilized to study the effect of Capmul (medium chain glycerides) on the absorption of a selection of beta-lactam and aminoglycoside antibiotics. All tested non-orally available beta-lactam antibiotics (cefamandole, cefotaxime, moxalactam, cefoxitin, mezlocillin, carumonam, penicillin G and amdinocillin) showed increased absorption enterally in rats and rectally in rabbits when formulated with Capmul. The orally available beta-lactam antibiotics, cephalexin and cephradine, were not enhanced in their enteral or rectal absorption by Capmul in the two model systems. Ampicillin absorption was enhanced rectally and enterally by Capmul. Rectal absorption of the aminoglycoside antibiotics, tobramycin and gentamycin, was enhanced by Capmul while enteral absorption was not.