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PubMed1991

Enhancement of dissolution and absorption of mefenamic acid by egg albumin.

The dissolution behavior and absorption of mefenamic acid following oral and rectal administration from drug:egg albumin solid dispersions have been studied in comparison with those of the drug alone. The interaction of drug with egg albumin in aqueous solution and solid state were examined by solubility analysis, dialysis experiments, and X-ray diffractometry. The results showed that the dissolution rate of mefenamic acid, and also the release of drug from witepsol H-15 suppositories, were significantly increased by using egg albumin:drug solid dispersions. Although egg albumin:drug solid dispersion enhanced the mean serum levels and the area under serum concentration-time curves after oral and rectal administration compared with those of the drug alone, no significant differences were found between the mean residence time values of drug and its solid dispersion. It was also noted that the extent of bioavailability of mefenamic acid and its solid dispersion following oral administration was significantly greater than that following rectal administration.

Administration, Rectal↗
PubMed2001

Symptom control in cancer patients: the clinical pharmacology and therapeutic role of suppositories and rectal suspensions.

Rectally administered medications are essential in palliative medicine, particularly in the last days of life. They are underutilized. The pharmacology of rectally administered medications relates not only to the medication but also to the suppository base, additives, drug ionization, p K(a), absorptive surface of the rectum, and rectal health. The pharmacokinetics may differ from those of orally administered medications owing to reduced hepatic first-pass clearance. In this review the pharmacology of rectally administered palliative medications is reviewed and the use of individual drugs is outlined.

Administration, Rectal↗
PubMedDate not supplied

Rectal administration of propylthiouracil in suppository form in patients with thyrotoxicosis and critical illness: case report and review of literature.

OBJECTIVE: To report the successful management of thyrotoxicosis in a seriously ill 47-year-old man with a perforated gastric ulcer in whom oral intake was contraindicated. METHODS: Our patient was treated with 400 mg of propylthiouracil (PTU) every 6 hours in the form of specially prepared suppositories for rectal administration, together with intravenously infused esmolol. RESULTS: We were able to demonstrate substantial absorption of PTU administered by means of rectal suppositories. Serum levels of PTU were maintained within the high therapeutic range for 5 days until the patient was able to tolerate orally administered therapy. The patient improved clinically during this treatment. CONCLUSION: This case strongly supports the rectal administration of PTU in suppository form as an appropriate alternative route in any patient with thyrotoxicosis, including the critically ill patient, when oral administration is not possible.

Administration, Rectal↗
PubMed1998

Avoidance of hepatic first-pass effect in the rabbit via rectal route of administration.

To assess avoidance of hepatic first-pass effect of drugs, we undertook in situ experiments using rectal administration of lidocaine in the rabbit. We also employed in situ duodenal route to estimate first-pass metabolism across the gastrointestinal mucosa. Rabbits were administered lidocaine HCl intravenously (i.v., 50 mg/20 min) and portally (i.p.v., 33.3, 16.7, 8.3 mg/20 min) and avoidance of hepatic first-pass effect (Fh) was calculated from the area under curve (AUC). Fh was about 30% and did not vary with increasing i.p.v. dose. Intravenous and i.p.v. administration was followed by duodenal (i.d.) or rectal (i.r.) administration and the absorption (fa), Fh, and avoidance of first-pass effect in the duodenal mucosal membrane (Fm) were determined. With i.d. administration, lidocaine was absorbed completely with negligible first-pass effect in the mucosa (Fm=1). On the other hand, while lidocaine was also absorbed almost completely via the i.r. route, avoidance of first-pass effect was 60%, representing twice the bioavailability via i.d. administration. On the basis of these data, assuming that the first-pass effect in the rectal mucosa was negligible, we estimate the fraction of rectal venous drainage bypassing the portal circulation and thus hepatic metabolism (fnh) to be about 40%.

Administration, Rectal↗
PubMed1991

Effects of oral phosphocysteamine and rectal cysteamine in cystinosis.

Diurnal variation in leucocyte cystine and the effects of equimolar single doses of oral phosphocysteamine and rectal cysteamine were studied in eight patients with cystinosis, aged 1.8-16.5 years. No significant diurnal variation in leucocyte cystine was found. Absorption of cysteamine was reduced after rectal administration compared with the oral dose: mean (SD) peak concentration 17.2 (6.3) mumol/l v 36.4 (5.5) mumol/l at 40 min and mean (SD) area under the curve 22.3 (14.3) v 59.4 (33.1) mumol/h/l. Oral phosphocysteamine significantly reduced the mean (SD) leucocyte cystine from 8.09 (0.47) to 3.26 (1.48) nmol 1/2 cystine/mg protein at three hours. At 12 hours the mean leucocyte cystine was significantly lower than the pretreatment concentration. Rectal cysteamine did not significantly reduce the mean leucocyte cystine concentration. In conclusion, phosphocysteamine suspension may be administered every 12 hours. Rectal cysteamine administration is feasible but higher doses are required before efficacy can be judged.

Administration, Oral↗
PubMed1996

Pharmacokinetic aspects of rectal formulations of temazepam.

An in vitro/in vivo study was carried out with different rectal formulations of temazepam. Pharmacokinetic data were determined in a cross-over study in 10 volunteers after rectal administration of 10 mg temazepam as a polyethylene glycol based suppository (selected from in vitro data), a liquid-filled capsule and a micro-enema respectively, using oral administration of a liquid-filled capsule as a reference. Serum levels of temazepam indicate an instantaneous and complete release from the micro-enema (Frel = 0.94 +/- 0.21, Cmax 205 +/- 36.9 micrograms/l, tmax 0.49 +/- 0.31 hour) and a slower but complete release of temazepam from the suppository (Frel = 1.10 +/- 0.25, Cmax 202 +/- 41.3 micrograms/l, tmax 1.48 +/- 0.41 hour). A high interindividual variation in absorption profiles was observed after rectal administration of the liquid-filled capsule (Frel 0.72 +/- 0.36, Cmax 182 +/- 122 micrograms/l, tmax 4.08 +/- 4.28 hour), which makes it less suitable for rectal use. The micro-enema and suppository appear to be useful as rectal formulations for temazepam.

Administration, Rectal↗
PubMed1983

Bioavailability of rectally administered carbamazepine suspension in dogs.

The relative bioavailability of an investigational carbamazepine suspension was studied following rectal administration in dogs. Doses of carbamazepine, 20 mg/kg, were given to six dogs. The routes of administration were oral tablet, oral suspension, and rectal suspension. There was no significant difference (p greater than 0.05) in total absorption, as indicated by the area under the serum concentration-time curve between the oral and rectal suspensions. The notable differences between the oral suspension and the rectal suspension were in the maximum serum concentration achieved and the time to achieve this maximum serum concentration. This is due to a prolonged absorption of carbamazepine given rectally, which may limit the ability to achieve therapeutic serum concentrations rapidly. Carbamazepine suspension given rectally may be a satisfactory alternative when administration by the oral route is not possible.

Animals↗
PubMed1988

Pharmacokinetics of ketamine HCl and metabolite I in the cat: a comparison of i.v., i.m., and rectal administration.

Ketamine HCl [2-(o-chlorophenyl)-2-(methylamino) cyclohexanone HCl] concentrations in whole blood were used to study the pharmacokinetics of i.v., i.m., and rectal administrations, at a dose of 25 mg/kg, in normal domestic cats. Absorption was rapid with both the i.m. and rectal routes. Systemic availability was 51% (SEM 10) for the i.m. dose and 43.5% (SEM 6.1) for the rectal dose. The first-pass effect had a minimal influence on the metabolism of ketamine HCl administered rectally. The elimination rate constant (beta) of the drug was statistically similar in the i.v., i.m., and rectal groups, at a 95% level of significance (P less than 0.05). At the dosage rates studied, ketamine HCl produced an anesthetic effect in the cat following i.v., i.m. and rectal administration.

Administration, Rectal↗
PubMed1984

Absorption and secretion of fluid and electrolytes by the rectum.

Although the amounts of ions and water absorbed and secreted by the rectum are small compared to those of other parts of the colon, rectal epithelium is capable of generating and maintaining considerable ionic gradients. Absorption of Na+ and Cl- and secretion of K+ and HCO-3 leads to relatively low concentrations of the former and high concentrations of the latter within the lumen. Detailed examination of the transport processes indicates that the epithelial mechanisms can be interpreted in terms of ionic movements through transcellular and paracellular pathways. These results show that the epithelium is relatively tight and largely amiloride-sensitive. Active Na+ absorption and apparent active K+ and HCO-3 secretion occur. The secretion of HCO-3 is related to Cl- and organic anion absorption. Mineralocorticoids increase the transepithelial potential difference (p.d.) as well as stimulating Na+ absorption and K+ secretion. Rectal epithelium may, with various physiological or pathological stimuli, become overtly secretory of a predominantly NaCl containing fluid but it remains uncertain whether some secretion is normally present although masked by absorption.

Animals↗
PubMed1988

Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (Part I).

Rational pharmacotherapy is dependent upon an understanding of the clinical pharmacokinetic and pharmacodynamic properties of the drugs employed. Although the available data on drug biodisposition and action in the neonate have increased considerably in the last few years, pharmacokinetic-pharmacodynamic interactions for many drugs remain poorly understood. The ontogeny of drug absorption, distribution, metabolism, and elimination are addressed in this review. Drug absorption from any site depends upon both the physicochemical properties of the drug and a variety of patient factors. Absorption of orally administered drugs may be affected by changes in gastric acidity and emptying time as well as by bile salt pool size, bacterial colonisation, and extraintestinal disease states such as congestive heart failure. Factors affecting drug absorption following intramuscular, percutaneous, and rectal administration are also discussed. Drug distribution in the neonate is influenced by a variety of important and predictable age-dependent factors. The developmental aspects of protein binding and body water compartments are described. Additionally, hepatic drug metabolism assumes an important role in understanding the pharmacokinetic and pharmacodynamic properties of many compounds. Certain biotransformation pathways, including hydroxylation by the P450 mono-oxygenase system and glucuronidation, demonstrate only limited activity at birth, while other pathways, such as sulphate or glycine conjugation, appear very efficient at birth. Elimination of drugs excreted unchanged in the urine is dramatically reduced in the newborn, compared with older infants and children, due to immaturity of both glomerular filtration and tubular secretory processes. The glomerular filtration rate remains markedly reduced prior to 34 weeks gestational age, increasing as a function of post-conceptual age until adult values are achieved by approximately 2.5 to 5 months of age. Tubular secretory capacity is also limited at birth, approaching adult values by approximately 7 months of age. Published reports describing the pharmacokinetics and pharmacodynamics of commonly used drugs in the neonatal period, as well as differences in drug biodisposition among premature infants, full term neonates, and older infants and children, are reviewed. Our recommendations for neonatal drug therapy are based upon a critical interpretation of these data, an understanding of fetal development and maturational processes, and an understanding of how disease states may affect drug biodisposition in the neonate.

Absorption↗
PubMed1984

Lumen perfusion of the human rectum in situ: a method to study mechanisms for rectal drug transport in humans.

A lumen perfusion system was developed to study rectal transport mechanisms in humans. With this technique it is possible to perfuse a well-defined area of the rectum wall under single-pass and recirculation conditions. Sodium benzoate was used as a test drug. After absorption, sodium benzoate is conjugated with glycine to give hippuric acid which is rapidly eliminated (t 1/2 = 0.5 h). Due to the short half-life it is possible to reach a steady-state concentration within 2.5 h of perfusion. Plasma concentrations of hippuric acid were determined by HPLC. The absorption influx of sodium benzoate per unit area (phi in) could be calculated using the steady-state concentration of hippuric acid during rectal perfusion, the separately measured total body clearance after intravenous injection, and a designated absorption surface of the rectum. It was shown that with this technique reproducible phi in values within one subject could be obtained. Four volunteers were perfused with four different solutions of sodium benzoate, and it was found that phi in was proportional to the four concentrations used. In the case of recirculation perfusion (two volunteers), it was found that the amount of the perfusate lost equalled the amount absorbed into the general circulation. Therefore, the possibility of major drug accumulation in the rectal lumen or mucosa could be excluded. The perfusion technique elaborated in the present study can be used to investigate the mechanism of rectal absorption in humans as well as the factors that may influence this process.

Benzoates↗
PubMed1987

Treatment of childhood epilepsy with rectal valproate: case reports and pharmacokinetic study.

Two children with status epilepticus were treated successfully by the rectal administration of valproate (VPA), and complete seizure control was obtained in one patient without severe side effects. In addition, there was no essential difference in pharmacokinetics between rectal and oral administration of VPA as determined by computerized simulation of plasma concentration data of VPA after rectal administration in two healthy adults or an epileptic child. Although these findings suggest that the early absorption of VPA within 30 minutes of rectal administration is slightly more rapid than that of oral administration, rectal VPA seems to be unsuitable for the first choice in the treatment of status epilepticus, since it has not so immediate effects as intravenous administration of DZP.

Administration, Rectal↗
PubMed1998

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 3rd Communication: suppositories.

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after rectal administration of tramadol suppositories (Tramal) were determined in a balanced crossover study in 10 female volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one rectally (1 suppository) and one intravenously (2 ml of a solution for injection). The formulations were administered in the morning, the washout period was one week. Serum concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability was calculated model-independently. The extent of the absolute bioavailability (F) of tramadol in the suppositories, based on AUC data, was 77.0% (point estimate; n = 10) with a 95% confidence interval of 70.8-83.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2933 +/- 304 h.ng/ml (rectal) and 3775 +/- 446 h.ng/ml (i.v.) [mean +/- SD; n = 10]. Optimal curve fitting of the serum concentration data after rectal administration presupposed the existence of two absorption sites with different absorption rates and lag times. Under this premise the absorption half-lives were t1/2,ka;1 = 1.7 h (median; range: 1.1-3.1 h) and t1/2,ka;2 = 0.98 h (0.35-1.9 h), and the corresponding lag times were t0;1 = 0 h (0-0.37 h) and t0;2 = 0.66 h (0.31-3.5 h). The relative portion of the more rapidly absorbed quantity of tramadol varied between 9.2 and 50% (median: 28%). The maxima of the serum concentration curves were reached 2-6 h after rectal administration; the means of the individual maxima were 294 +/- 50 ng/ml (Cmax) and 3.3 +/- 1.3 h (tmax). There were large differences in the distribution rate between the volunteers. The means of the half-life of the slower distribution (t1/2, alpha) were 1.38 +/- 0.47 h (rectal; n = 10) and 1.78 +/- 0.63 h (i.v.; n = 7). In the terminal phase the biological half-life (t1/2, beta) was 5.7 +/- 1.0 h (rectal) and 5.7 +/- 0.9 h (i.v.), respectively. The values determined after i.v. injection for the total distribution volume and the total clearance were 216 +/- 231 (Vd, beta) and 447 +/- 56 ml/min (Cltot). The results show that after rectal administration of the tramadol suppositories the absorption of the active ingredient is rapid enough for therapeutic purposes and that the extent of the absolute bioavailability is higher than after oral administration of tramadol-HCl, probably due to a reduced first-pass metabolisation after rectal administration.

Adult↗
PubMed1984

Minimal changes in hypothalamic temperature accompany microwave-induced alteration of thermoregulatory behavior.

This study probed the mechanisms underlying microwave-induced alterations of thermoregulatory behavior. Adult male squirrel monkeys (Saimiri sciureus), trained to regulate the temperature of their immediate environment (Ta) behaviorally, were chronically implanted with Teflon reentrant tubes in the medical preoptic/anterior hypothalamic area (PO/AH), the brainstem region considered to control normal thermoregulatory processes. A Vitek temperature probe inserted into the tube measured PO/AH temperature continuously while changes in thermoregulatory behavior were induced by either brief (10-min) or prolonged (2.5-h) unilateral exposures to planewave 2,450-MHz continuous wave (CW) microwaves (E polarization). Power densities explored ranged from 4 to 20 mW/cm2 (rate of energy absorption [SAR] = 0.05 [W/kg]/cm2]). Rectal temperature and four representative skin temperatures were also monitored, as was the Ta selected by the animal. When the power density was high enough to induce a monkey to select a cooler Ta (8 mW/cm2 and above), PO/AH temperature rose approximately 0.3 degrees C but seldom more. Lower power densities usually produced smaller increases in PO/AH temperature and no reliable change in thermoregulatory behavior. Rectal temperature remained constant while PO/AH temperature rose only 0.2-0.3 degrees C during 2.5-h exposures at 20 mW/cm2 because the Ta selected was 2-3 degrees C cooler than normally preferred. Sometimes PO/AH temperature increments greater than 0.3 degrees C were recorded, but they always accompanied inadequate thermoregulatory behavior. Thus, a PO/AH temperature rise of 0.2-0.3 degrees C, accompanying microwave exposure, appears to be necessary and sufficient to alter thermoregulatory behavior, which ensures in turn that no greater temperature excursions occur in this hypothalamic thermoregulatory center.

Animals↗
PubMed2001

Hypoxic brain damage after intramuscular self-injection of diclofenac for acute back pain.

We present a case of hypoxic brain damage that occurred after intramuscular injection of diclofenac due to a severe anaphylactic reaction. A 38-year-old nurse treated herself for acute lower back pain with 100 mg diclofenac intramuscularly. Five minutes later, she collapsed and developed coma and respiratory arrest. After cardiopulmonary resuscitation she was transferred to hospital. On admission she was comatose and received controlled ventilation of the lungs. Magnetic resonance imaging and computerized tomography showed signs of hypoxic brain injury and the patient died from central cardiopulmonary failure 7 days later. Intramuscular treatment with non-steroidal anti-inflammatory drugs such as diclofenac has rare but potentially severe side-effects. Therefore, intramuscular injections are inappropriate and should be replaced with oral or rectal treatment, which has similar absorption profiles.

Acute Disease↗
PubMed1997

Utility of a rectal suppository containing the antiepileptic drug zonisamide.

A suppository of zonisamide (ZNS) was investigated from the viewpoint of pharmaceutical evaluation, pharmacokinetics and pharmacological effect. Two types of ZNS suppositories were prepared. One used Witepsol (H-15:S-55 = 3:1) as a lipophilic base and the other polyethylene glycol (PEG, 4000:1500 = 4:1) as a hydrophilic base. The in vitro release rate of ZNS from the PEG suppository was significantly rapid compared with that of ZNS from Witepsol. Male Wistar rats were administered ZNS (20 mg/kg) using an intravenous, oral or rectal (PEG or Witepsol) route. The absorption of ZNS from the PEG suppository was more rapid than that of ZNS from the Witepsol suppository or from the oral preparation. The peak plasma concentration (Cmax) after a rectal administration of ZNS with Witepsol or PEG suppository was significantly higher than that after the oral administration of ZNS. However, the bioavailability of the three preparations was approximately 100%. Male ICR mice were administered ZNS (80 mg/kg) using the oral or rectal (PEG or Witepsol) route. A positive correlation was observed between the electroshock seizure (ES) threshold and ZNS concentration in plasma or brain. Further, there was no significant difference in the ES threshold or the ZNS concentration in plasma or brain among the three preparations. These results indicate that a ZNS suppository is a very useful preparation from the viewpoint of both pharmacokinetics and pharmacological action.

Administration, Oral↗