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PubMed1995

Plasma concentrations after high-dose (45 mg.kg-1) rectal acetaminophen in children.

Although the recommended dose of rectal acetaminophen (25-30 mg.kg-1) is twice that for oral administration (10-15 mg.kg-1), the literature justifies the use of a higher dose when acetaminophen is administered via the rectal route. We measured venous plasma acetaminophen concentrations resulting from 45 mg.kg-1 of rectal acetaminophen in ten ASA 1, 15 kg paediatric patients undergoing minor surgery with a standardized anaesthetic. After induction of anaesthesia, a single 650 mg suppository (Abenol, SmithKline Beecham Pharma Inc.) was administered rectally. Plasma was sampled at t = 0, 15, 30, 45, 60, 90, 120, 180, 240 min in the first five patients and at t = 0, 30, 60, 90, 120, 180, 240, 300, 420 min in the subsequent five. Acetaminophen plasma concentrations were determined using a TDxFLx fluorescence polarization immunoassay (Abbott Laboratories, Toronto, Ontario). The maximum plasma concentration was 88 +/- 39 mumol.L-1 (13 +/- 6 micrograms.ml-1) and the time of peak plasma concentration was 198 +/- 70 min (mean +/- SD). At 420 min, the mean plasma concentration was 46 +/- 18 mumol.L-1 (7.0 +/- 0.9 micrograms.ml-1). No plasma concentrations associated with toxicity (> 800 mumol.L-1) were identified. A 45 mg.kg-1 rectal dose of acetaminophen resulted in peak plasma concentrations comparable with those resulting from 10-15 mg.kg-1 of oral acetaminophen at three hours after suppository insertion. It is concluded that the delayed and erratic absorption of acetaminophen after rectal administration leads to unpredictable plasma concentrations. Rectal acetaminophen will not be consistently effective for providing rapid onset of analgesia in children.

Absorption↗
PubMed1996

Pharmacodynamics and pharmacokinetics of recombinant human granulocyte colony-stimulating factor (rhG-CSF) after administration of a rectal dosage vehicle.

The pharmacodynamic activities (leukopoietic effect) and pharmacokinetics of recombinant human granulocyte colony-stimulating factor (rhG-CSF) administered rectally in various doses as hollow-type suppositories were investigated in rabbits. Three kinds of rhG-CSF hollow-type suppositories were employed: suppository I containing rhG-CSF (100-1000 micrograms/kg) in 10 mM acetate buffer solution (ABS) at pH 4.0, suppository II containing rhG-CSF in ABS with alpha-cyclodextrin (alpha-CyD) as an absorption-enhancing agent, and suppository III containing lyophilized rhG-CSF powder. We found that the total count of leukocytes in peripheral blood (total blood leukocyte count) and serum granulocyte colony-stimulating factor (G-CSF) concentration showed a dose-dependent increase. Consequently, the area under the increased total blood leukocyte count-time curve (AUI), an index of pharmacodynamic activity, and the area under the serum G-CSF concentration-time curve (AUC), a pharmacokinetic parameter, increased with an increase in the rhG-CSF dose administered rectally. Good correlation was found between AUL and AUC; thus, it is concluded that an increase in AUC leads to an increase in the effect of rhG-CSF in inducing leukopoiesis in rabbits following rectal administration. We report for the first time the rectal absorption of rhG-CSF using a new rectal dosage vehicle (rhG-CSF hollow-type suppository) and its leukopoietic effect. The rhG-CSF hollow-type suppository is found to be a promising drug delivery system.

Administration, Rectal↗
PubMed1977

Antipyretic therapy. Comparison of rectal and oral paracetamol.

The absorption of paracetamol from syrup, tablet and two different suppository bases was compared in six adult volunteers using urinary excretion measurements. The total amount of paracetamol and its metabolites excreted and the peak excretion rates were lower from the suppository bases than from the oral dosage forms. Absorption was a little better from a polyethylene glycol suppository base than from a triglyceride base. The antipyretic efficacy of a paracetamol syrup and suppository at a dose of 10 mg/kg was compared in 30 children between the age of 4 months and 12 years, who had infections and a rectal temperature above 38.5 degrees C. Both dosage forms produced a significant decrease in temperature, the greatest fall being about 2 hours earlier with the oral dosage form. The syrup also seemed to be significantly (p less than 0.05) more effective (maximum fall of temperature 1.58 degrees C) in reducing fever than the suppository, which produced its greatest fall of temperature (1.24 degrees C) six hours after insertion of the suppository. From the practical point of view both forms can be regarded as safe and effective antipyretics.

Acetaminophen↗
PubMed1999

Pharmacokinetics of paracetamol in adults after cardiac surgery.

The pharmacokinetics of paracetamol in adults after cardiac surgery have not been described. Twenty patients were randomized to receive either paracetamol 2 g through a nasogastric tube and as a suppository eight hours later or vice versa. Arterial blood samples were taken at 0.5, one, two, four, six and eight hours after dosing. Each patient was studied for 16 h. There were 16 males and three females. One patient was excluded because of sampling errors. The mean age was 59 (SD 8) years and the mean weight 84 kg (16). The time-concentration profiles for each individual were used to estimate pharmacokinetic parameters using a non-linear mixed effects model (NONMEM). Population parameter estimates with coefficient of variation (CV%), standardized to a 70 kg person, for a one-compartment model with first order input, lag time and first order elimination were volume of distribution 127l (28) and clearance 26.4 l/h (29) Rectal paracetamol had an absorption half-life (Tabs) of 2.02 h (31) with a lag time of 0.28 h. The absorption half-life for the oral preparation was 1.49 h (81) with a lag time of 0.17 h. The relative bioavailability of the rectal compared to the oral formulation was 0.98 (18). Concentrations after either nasogastric or rectal paracetamol 2 g were below a target concentration of 10 mg/l, which is associated with analgesia. Absorption after nasogastric administration was slow compared to healthy adults (Tabs 0.06 to 0.7 h) and the bioavailability was half that expected, due to nasogastric loss. Parameter estimates had large variability. Paracetamol is unlikely to have useful clinical impact in the majority of patients when standard doses (6 g/day) are given on day 1 after cardiac surgery.

Acetaminophen↗
PubMed1989

Diarrhoea in jaundiced neonates treated with phototherapy: role of intestinal secretion.

Thirty jaundiced neonates with diarrhoea who were being treated with phototherapy and 30 matched control infants were studied to try and find out the cause of the diarrhoea. Faecal osmolality and electrolyte concentrations were measured, which gave clear evidence that the diarrhoea arose from intestinal secretion. Rectal water and electrolyte absorption in 10 jaundiced infants receiving phototherapy, in 10 jaundiced infants not receiving phototherapy, and in 10 healthy controls was measured with a rectal dialysis bag. A further group of eight jaundiced infants was also studied both during and after phototherapy to document the reversal of ion transport changes. Absorption of water, sodium chloride, and potassium was significantly impaired in the patients receiving phototherapy compared with each of the control groups. Such impairment was transient, as it was not apparent when the jaundice faded and phototherapy was stopped. These data show that the colon plays a part in the pathogenesis of secretory diarrhoea and that both hyperbilirubinaemia and phototherapy are necessary for such an effect to develop.

Diarrhea, Infantile↗
PubMed1992

Bioavailability of ibuprofen from oral and suppository preparations in rats.

Bioavailability of ibuprofen (15 mgkg-1) from oral and suppository dosage forms was investigated. Three different combinations of PEG 4000 and 1000 and theobroma oil were used as suppository bases. Oral administration gave higher values for mean residence time (MRT) and absolute bioavailability (F) compared to suppository dosage forms. The theobroma oil base was associated with lower maximum plasma concentration (cpmax), area under the concentration time curve (AUC) and F values compared to the other bases but differences were not significant (P greater than 0.05). Ibuprofen appears to be strongly retained by the lipophilic base, thereby limiting its diffusion through the rectal mucosal membrane. The absorption profile was slightly improved for the three PEG combination bases but were inferior to oral dosing. It is suggested that the relatively smaller size of the rectal mucosal membrane compared to the small intestine was primarily responsible for limiting the rate/extent of ibuprofen absorption. The absorption profile from the suppository preparations may be enhanced by the appropriate selection of the bases and their additives.

Administration, Oral↗
PubMed2003

Rectal ropivacaine is absorbed proportionally to the dose, with low intraindividual variability.

AIMS: This study investigated the absorption characteristics and the tolerability of rectally administered ropivacaine, a local anaesthetic, intended as a new local therapy for ulcerative colitis. METHODS: Thirty-two healthy volunteers participated in a randomized, placebo-controlled study. In study phase 1 (n = 16, double-blind, crossover) single rectal doses of ropivacaine corresponding to 50, 100 and 200 mg base were given as 20-ml gel enemas. Eight of these subjects also received an i.v. infusion corresponding to 20 mg (2H3)ropivacaine base given with the last rectal dose. In study phase 2 (n = 16, single-blind, crossover) the same rectal doses were given but formulated in 20, 40 and 80 ml gel, respectively. Peripheral venous plasma samples and urine were collected over 12 h after dosing and analysed for ropivacaine base by gas chromatography and (2H3)ropivacaine by gas chromatography-mass spectrometry. Ropivacaine and metabolites were analysed in urine by reversed phase liquid chromatography. RESULTS: AUC was proportional to the dose with a point estimate [95% confidence interval (CI)] for the increase, after doubling the dose, of 1.91 (1.66-2.20) and 1.95 (1.78-2.13) in study phases 1 and 2, respectively. The increase in Cmax was also proportional to the dose with corresponding results of 1.76 (1.52-2.04) and 1.84 (1.70-1.99). The volume of the rectal formulation had no influence on either the extent or the time course of absorption. The mean (s.d.) absolute bioavailability (%F) was 56 (18)%. AUC and Cmax showed a two- to three-fold lower intra- than interindividual variability. Zero-order kinetics dominated the first 4 h of the absorption phase. Thereafter first-order kinetics were observed. The terminal half-lives were similar between the rectal doses and were longer than that after the i.v. administration, indicating an absorption-dependent half-life. The main urinary metabolite was 3-hydroxyropivacaine corresponding to about 23% of the dose. The subjects had no difficulties in retaining the doses and rectal administration of ropivacaine was well tolerated, both locally and systemically. CONCLUSIONS: Plasma drug concentrations were proportional to the dose after rectally administered doses corresponding to 50-200 mg ropivacaine base in a gel formulation. The drug was well-tolerated. Mean bioavailability was about 60% and not influenced by variations in the enema volume. Initial absorption seemed to follow zero-order kinetics and then first-order kinetics after about 4 h. Cmax and AUC showed considerably less intra- compared with inter-individual variability, resulting in more consistent plasma concentrations within subjects.

Administration, Rectal↗
PubMed1988

Absorption of water and sodium and activity of adenosine triphosphatases in the rectal mucosa in tropical sprue.

In 10 southern Indian patients with tropical sprue, in vivo dialysis showed a defect of absorption of water and sodium from the rectum, when compared with 11 healthy volunteers. Sodium-potassium-ATPase activity, measured in homogenates of rectal biopsies, was significantly diminished in patients with sprue. Magnesium-ATPase and alkaline phosphatase were normal in biopsy homogenates. Decreased activity of colonic sodium-potassium-ATPase may contribute to diarrhoea in some patients with tropical sprue.

Humans↗
PubMed1985

[Pharmacokinetics of ceftizoxime suppository in experimental animals].

Ceftizoxime suppository (CZX-S) was administered rectally to mice, rats and dogs, and the pharmacokinetics were studied in comparison with those after intravenous, intramuscular and subcutaneous administration of ceftizoxime (CZX). Absorption of CZX given rectally was rapid in all animals, similar to intramuscular or subcutaneous administration. The peak serum levels of CZX in mice, rats and dogs when administered rectally at a dose of 25 mg/kg were 23.1 micrograms/ml at 7.5 minutes, 23.5 micrograms/ml at 15 minutes and 25.2 micrograms/ml at 15 minutes, respectively. These values were about 76%, 68% and 42% of the values for subcutaneous or intramuscular administration in mice, rats and dogs at the same respective doses. Urinary recoveries of CZX after rectal administration of 25 mg/kg were 44.2% (0-12 12 hours) in rats and 27.7% (0-6 hours) in dogs, and 2.7% (0-6 hours) of the dose was excreted into bile fluid in rats. Organ distribution of CZX when administered rectally to rats was similar in distribution pattern to that of muscular administration, although its concentrations in various organs were slightly lower than those for intramuscular administration, as was the case for serum concentration. Serum concentrations of CZX were proportionately elevated with dose when dogs were rectally administered CZX-S in doses of 12.5, 25 and 50 mg/kg. In the case of multiple administrations (t.i.d. for 10 days) of CZX-S to dogs, no remarkable difference was found in serum concentrations of CZX in comparison with single doses, and no accumulation of CZX was demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1998

Relative bioavailability and plasma paracetamol profiles of Panadol suppositories in children.

OBJECTIVE: To determine the relative bioavailability and plasma paracetamol concentration profiles following administration of a proprietary formulation of paracetamol suppositories to postoperative children. METHODOLOGY AND RESULTS: Study A-eight children undergoing minor surgery had blood samples collected following the rectal administration of either a 250 mg or 500 mg paracetamol suppository on one day and an equivalent oral dose on the following day. A mean dose of 13 mg/kg gave a mean Cmax (Tmax) of 7.7 mg/L (1.6 h) and 4.9 mg/L (2.0 h) following oral and rectal administration, respectively. The mean relative rectal bioavailability was 78% (95% confidence interval of 55-101%). Study B-20 children undergoing tonsillectomy and/or adenoidectomy were randomly assigned to receive a postoperative dose of 500 mg of paracetamol either as 2 x 250 mg liquid filled or 1 x 500 mg hard wax Panadol suppository. A mean dose of 25 mg/kg produced mean maximum plasma paracetamol concentrations of 13.2 mg/L and 14.5 mg/L at 2.1 and 1.9 h for the hard and liquid filled suppository, respectively. The absorption rate constants and areas under the curves suggested no difference in the rate or extent of absorption between the two formulations. CONCLUSION: Absorption of paracetamol following rectal administration of Panadol suppositories to postoperative children is slower and reduced as compared to oral therapy. The hard wax and liquid filled products have similar absorption characteristics. The usually quoted antipyretic therapeutic range for paracetamol is 10-20 mg/L, although 5 mg/L may be effective. A single rectal dose of 25 mg/kg will obtain this lower concentration within 1 h of administration and maintain it for up to 6 h. When given in an appropriate dose for analgesia, maximum plasma paracetamol concentrations would be available in the immediate postoperative period if the rectal dose was given 2 h before the planned end of the procedure.

Acetaminophen↗
PubMed1996

Rectal controlled-release morphine: plasma levels of morphine and its metabolites following the rectal administration of MST Continus 100 mg.

Eight patients undergoing major maxillary surgery were given sustained-release morphine (100 mg MST Continus) rectally, immediately after induction of general anaesthesia. Blood samples for assay were taken just prior to morphine administration, together with a further 11 samples over the following 24 h. Assay of the plasma for morphine, morphine-3-glucuronide and morphine-6-glucuronide was carried out using a validated high-performance liquid chromatography technique. Morphine Tmax ranged from 3 h to 12 h (median 6 h), Cmax 8.0-40.0 ng/ml and AUC0-24 90.1-429.7 ng/h/ml in subjects offering blood samples over the 24-h period. Likewise, morphine-3-glucuronide Tmax ranged from 3 h to 24 h (median 9 h), Cmax 153-370 ng/ml and AUC0-24 2776-4390 ng/h/ml. Morphine-6-glucuronide Tmax ranged from 8 h to 12 h (median 10 h), Cmax 24-59 ng/ml and AUC0-24 137-803 ng/h/ml. Morphine and morphine metabolite AUC0-24 ratios were calculated, but they did not correlate with analgesic needs. The AUC0-24 ratios were similar to those following oral and rectal dosing in other studies involving cancer patients. The wide variation of individual morphine and metabolite plasma levels, and their AUC ratios indicates considerable interpatient variability in the absorption and metabolism of rectal sustained-release morphine. This large interpatient variation may indicate that it is not suitable for acute pain, because analgesic requirements change much more rapidly than in the chronic pain situation where individual patient titration can take place.

Administration, Rectal↗
PubMed1981

Pharmacokinetics of diazepam administered rectally in geriatric patients: comparison of suppositories with rectal tubes in a cross-over study.

The pharmacokinetics of diazepam administered as suppositories or as a solution in rectal tubes were compared in six geriatric hospital patients. A single dose of 10 mg was administered in a cross-over study with a one week interval. There was no statistically significant difference in the bioavailability, the mean maximum serum concentration or the time of achievement of the maximum with these preparations. However, the peak serum concentration was somewhat higher with suppositories but the absorption was somewhat faster via rectal tubes. The serum N-desmethyldiazepam concentration increased during the whole 24 hour observation period, there was no difference between the preparations. Our results are in good agreement with most studies of the pharmacokinetics of diazepam. The basal substance of the suppository is of the utmost importance to the absorption of diazepam. The rectal tube for administration of diazepam did not have any advantage over the optimally formulated (a mixture of macrogols) suppository in geriatric patients. In fact, the use of rectal tubes is more expensive, the tube may not be completely emptied, and the solution may not be completely retained in the rectum.

Aged↗