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PubMed2004

The pharmacokinetics of oxycodone.

Oxycodone is among the most commonly used opioid analgesics for the relief of moderate-to-severe pain and is pharmacodynamically comparable to morphine. Oxycodone is available in the United States in oral dosage forms and controlled-release tablets. Studies have demonstrated marked interindividual variation in the pharmacokinetics of oxycodone. The pharmacokinetics of oral oxycodone differs from oral morphine in that it has a higher bioavailability, a slightly longer half-life, and is hepatically metabolized by cytochrome P450 rather than undergoing glucuronidation. Understanding oxycodone pharmacokinetics favors safe and effective use of this analgesic in a wide variety of patients with different levels of organ function. A MEDLINE search was conducted to identify literature published between 1966 and May 2004 relevant to the pharmacokinetics of oxycodone. These publications were reviewed and the literature summarized regarding unique and clinically important elements of oxycodone disposition including its absorption profile (immediate release, controlled release, rectal administration, and intranasal administration), distribution, and its metabolism/excretion. Special populations, including children and those with liver/renal failure, have a unique oxycodone pharmacokinetic profile that must be taken into account in order to maximize analgesic efficacy and reduce the risk of adverse events.

Administration, Oral↗
PubMed1986

Acylcarnitines: drug absorption-enhancing agents in the gastrointestinal tract.

Acylcarnitines were tested as potential absorption-enhancing agents for drugs that are poorly absorbed from the gastrointestinal tract. Urethan-anesthetized Sprague-Dawley rats and conscious Beagle dogs were used. Palmitoyl-DL-carnitine was the most effective acylcarnitine tested, although significant increases in drug absorption were observed with acylcarnitines containing C12 through C18 fatty acid chains. Palmitoyl-DL-carnitine afforded significant increases in the absorption of cefoxitin, gentamicin, cytarabine, somatostatin analogue, and alpha-methyldopa. The response to palmitoyl-DL-carnitine was concentration dependent and reversible within 60-120 min. Histological examination of the intestinal tissue revealed no apparent change in mucosal structural integrity at doses of palmitoyl-DL-carnitine that resulted in increased drug absorption. The acylcarnitines were effective in increasing drug absorption from the small intestine and the rectal compartment of both rats and dogs. The data also demonstrated effectiveness with aqueous and solid dosage forms (Witepsol H-15 suppositories). The data suggest that acylcarnitines may be effective and safe absorption-enhancing agents for a variety of drugs.

Animals↗
PubMed1984

Fecal alpha 1-antitrypsin clearance in patients with inflammatory bowel disease.

We evaluated fecal clearance of alpha 1-antitrypsin (alpha 1-AT) as a method of detecting and quantitating intestinal protein loss in patients with inflammatory bowel disease. We investigated alpha 1-AT clearance (C alpha 1-AT) in 14 patients (seven with Crohn's disease, seven with ulcerative colitis) and in 10 children with gastrointestinal disorders and normal serum albumin values who served as controls. The inflammatory bowel disease patients were analyzed for nutritional status, intestinal absorption, disease activity and distribution, and presence or absence of rectal bleeding. alpha 1-AT was measured in stool (72-h collections) and serum by radial immunodiffusion, and the clearance was calculated. The mean C alpha 1-AT in patients with inflammatory bowel disease was significantly (p less than 0.05) higher than that of the controls. C alpha 1-AT in the former patients was inversely related to the serum albumin level (p less than 0.001), but not to disease activity, medications, absorption, nutritional status, or moderate rectal bleeding. In the patients with Crohn's disease there was a trend to increased C alpha 1-AT from only ileal to diffuse small intestinal disease involvement. We conclude that in patients with inflammatory bowel disease, fecal clearance of alpha 1-AT is a useful method for quantitating intestinal protein loss, and that moderate rectal bleeding does not affect the C alpha 1-AT determination.

Adolescent↗
PubMed1995

Pharmacokinetics and pharmacodynamics of oxycodone when given intravenously and rectally to adult patients with cancer pain.

The single-dose pharmacokinetics and pharmacodynamics of oxycodone administered by the intravenous and rectal routes were determined in 12 adult cancer patients with moderate to severe cancer pain (visual analog scale [VAS] score, approximately 5). Oxycodone was administered by the intravenous and rectal routes with open drug administration and a cross-over design. After single-dose intravenous administration (7.9 +/- 1.5 mg, mean +/- SD), the mean (+/- SD) terminal half-life was 3.4 h (+/- 1.1), the mean (+/- SD) plasma clearance was 45.4 L/h (+/- 10.1), and the mean (+/- SD) volume of distribution in the terminal phase was 3.0 L/kg (+/- 1.1). After rectal oxycodone (30 mg), the mean (+/- SD) absorption lag time was 0.52 h (+/- 0.29) and the mean (+/- SD) absolute bioavailability was 61.6% (+/- 30.2%). Intravenous oxycodone was associated with a rapid onset of pain relief (5-8 min) in contrast to the 0.5- to 1.0-h delay observed after rectal administration. However, rectal oxycodone provided analgesia of much longer duration (approximately 8-12 h) than did intravenous oxycodone (approximately 4 h). There were no significant differences (P > 0.05) in the incidence and severity of side effects between intravenous and rectal oxycodone. The marked interindividual variation observed in the pharmacokinetics and pharmacodynamics of oxycodone in this study emphasizes the need for individualized dosing regimens.

Administration, Rectal↗
PubMed1984

Absolute intramuscular, oral, and rectal bioavailability of alizapride.

A study was designed to estimate the absolute bioavailability of alizapride after intramuscular injection, oral administration as a solution or a tablet, and rectal administration as a suppository compared with that after intravenous injection. A balanced incomplete block-design trial was adopted. The intramuscular injection and the tablet administration showed identical results with those of the intravenous injection. On the contrary, the oral solution and the rectal suppository dosage forms gave lower absorption values, i.e., 75 and 61% of the dose administered was absorbed, respectively.

Administration, Oral↗
PubMed1999

Clinical assessment of positron emission tomography for the diagnosis of local recurrence in colorectal cancer.

BACKGROUND: The clinical value of positron emission tomography (PET) for the diagnosis of local pelvic recurrence of colorectal cancer was evaluated. METHODS: Computed tomography (CT) and magnetic resonance imaging (MRI) of the pelvis were performed at regular intervals in 23 patients who had undergone resection for colorectal cancer. The 23 patients had a total of 25 lesions. PET images of the 25 lesions and of six primary lesions in patients with rectal cancer were obtained. A differential absorption ratio (DAR) was calculated in order to examine the accumulation of [18F]2-fluoro-2-deoxy-D-glucose (18FDG) on PET images. Histological diagnoses of the pelvic masses were obtained by CT-guided needle biopsy. RESULTS: On CT or MRI, a pelvic mass with a spicular shape (n = 1) was non-recurrent, whereas a nodular or lumpy shape indicated a locally recurrent lesion (n = 10). Masses with a nodulospicular shape (n = 12) did not correlate with the histological features. On PET, 15 of 16 histologically proven local recurrences were imaged positively. By setting a DAR of 2.8 as a cut-off value, local recurrences could be diagnosed with 100 per cent accuracy. CONCLUSION: PET is a clinically useful tool for the detection of local recurrence of colorectal cancer, particularly for distinguishing between recurrence and granulation tissues in the pelvic cavity.

Adult↗
PubMed1987

Evaluation of portal circulation with radioisotopes in dogs.

The objective of the present study was to contribute to the development of a noninvasive method for the evaluation of portal circulation using rectally administered radiotracers in dogs. 99mTc absorption was previously checked in rabbits and the present study reports similar results in dogs. Circulation time between the terminal large bowel and the liver (RL-t) and heart (RH-t) was determined by external counting at the hepatic and cardiac level with a large-field computerized gamma camera. In 16 animals studied, average RL-t was 5.2 s and RH-t 8.6 s. In 3 animals with partial binding of the portal vein, RL-t increased to 32, 44 and 34 s. Being noninvasive and harmless, this method could be used to study portal circulation in several physiopathological conditions of the human liver.

Animals↗
PubMed1987

Current innovations in drug delivery.

It is almost twenty years since the attention of the pharmaceutical industry was focussed on an alternative strategy--improving existing medicines by better control of the site, duration and intensity of the drugs they contain. Whilst site specificity remains a major objective for future medicines, progress has mainly come from devices which modulate the duration and intensity of drug action. In their most advanced form, they will deliver their contents in response to a physiological or pathological demand such as a diabetic's glucose level. However, practical devices have been limited to passive dosage forms which either speed up or slow down the rate of systemic absorption in a controlled manner. Oral, rectal, percutaneous and parenteral routes have been energetically explored and several products have been successfully marketed. Oral administration has dominated invention. Future advances will embrace the concepts of variable or pulsed release in order to meet particular therapeutic criteria. Equally important will be the extension of transit time in order to increase the uptake of some poorly absorbed drugs, or to extend dosage intervals to twenty-four hours. Attempts to more closely approach constant release rates at the end of the release period, to devise efficient formulae which carry drug loadings in excess of eighty per cent, or to invent formulae which, whilst retaining precision, are cheaper and more easily manufactured are less innovative aspects of this important field. The commercial success of percutaneous presentation of glyceryl trinitrate has prompted further refinement of this principle and guidelines for exploitation are now clearer. The development of acceptable penetration enhancers remains an important element in extending this principle to a wide range of drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed2006

Novel mucosal insulin delivery systems based on fusogenic liposomes.

PURPOSE: Fusogenic liposomes (FLs) are unique delivery vehicles capable of introducing their contents directly into the cytoplasm with the aid of envelope glycoproteins of Sendai virus (SeV). The objective of this study was to evaluate the potential of FL to improve the mucosal absorption of insulin from rat intestinal membranes. METHOD: The FLs containing insulin were prepared by fusing insulin-loaded liposomes with inactivated SeV particles and were administered directly into the ileal, the colonic, and the rectal loops (10 IU/kg). RESULTS: The FL successfully enhanced the insulin absorption and induced a significant hypoglycemic effect following the colonic and the rectal administration without detectable mucosal damage. This enhancing effect of insulin absorption was further improved by increasing the amount of insulin loaded in the FL and by coencapsulating insulin-degrading enzyme inhibitor. In contrast, the insulin absorption was not increased by the ileal administration of FL because the mucous/glycocalyx layers overlaid on the ileal epithelium impede the fusion of FL to the intestinal mucosa. CONCLUSION: Our results indicated that FL is a useful carrier for improving the absorption of poorly absorbable drugs, such as insulin, via the intestinal tract.

Animals↗
PubMed1989

Ion transport and enteric nervous system (ENS) in rat rectal colon: mechanical stretch causes electrogenic Cl-secretion via plexus Meissner and amiloride-sensitive electrogenic Na-absorption is not affected by intramural neurons.

The initial phase of in vitro experiments in Ussing-type chambers on large intestine is characterized by short-circuit currents (ISC) declining from high starting values to a lower plateau within 0.5 h. The origin of this "initial ISC-transient" was investigated by ISC measurements on partially stripped segments of rat rectal colon. Transport was pre-stimulated in vivo by keeping animals in barbiturate-anesthesia for 5 h prior to tissue preparation. This procedure caused by endogenous aldosterone-liberation amiloride-sensitive Na-absorption to become the predominant electrogenic transport. The initial ISC-transient was abolished by tetrodotoxin (TTX, 1 microM), indicating a neuronal mediation of this phenomenon. In order to identify the transport which was subject to neuronal control, the amiloride-sensitive Na-absorption was measured during electrical field stimulation (bipolar rectangular pulses: 5 Hz, 1 ms, +/- 6 mA). There was no difference to unstimulated controls. In contrast, the initial ISC-transient was dependent on Cl in the bath following Michaelis-Menten-kinetics (KM = 20 mM) and could be prevented by 10 microM serosal bumetanide. Then, initial filling of the Ussing-chamber was imitated during the course of the experiment by removal and immediate re-addition of the bathing fluid. This procedure caused ISC-changes of similar appearance as the initial ISC-transient. To verify that indeed mechanical stretch is the sensory stimulus triggering the initial ISC-transient, the effect of small pressure oscillations was studied. This also produced an ISC-transient which was TTX-sensitive and was abolished after removal of the submucosal plexus Meissner by total stripping.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1982

Absorption of diazepam from the rectum and its effect on interictal spikes in the EEG.

Rectal administration of several different preparations of diazepam to a group of adult volunteer patients with epilepsy produced variable rates of absorption. Peak serum concentrations following 10 mg, 20 mg, and 30 mg of diazepam solution were achieved between 13-60 min, 10-120 min, and 30-90 min respectively. An experimental diazepam "solid solution" suppository was found to have significantly better absorption characteristics compared with the commercially available Valium suppository. Diazepam solution 20 mg was administered rectally in 10 adult epileptic patients with frequent spontaneous interictal spikes in their EEGs. A highly significant reduction in spike frequency was seen compared with placebo. The effect was most marked 10-20 min after administration of diazepam, when the mean spike count fell to 39 +/- 35 SD percent of the control value (p less than 0.01), and this corresponded with a mean serum diazepam level of 210 +2- 125 ng/ml.

Adolescent↗
PubMed1987

Moment analysis of intravenous, intraduodenal, buccal, rectal and percutaneous nifedipine in rats.

The pharmacokinetics and bioavailability of intravenous, intraduodenal, buccal, rectal and percutaneous nifedipine were studied in rats to evaluate the influence of route of administration. Plasma concentrations of nifedipine were determined by electron capture gas-liquid chromatography with preliminary oxidation of the drug to its pyridine analog. Pharmacokinetic evaluations were carried out by noncompartmental analysis of plasma concentration-time curves based on the statistical moment theory. The moments were computed by fitting a polyexponential function to the discrete time-course data of plasma concentration using the iterative least-squares method. A good computer fit to biexponential kinetics and a short mean residence time were observed after intravenous administration (i.v.). The linear distribution and disposition of nifedipine was found within the dosing range tested (0.025-0.100 mg/kg, i.v.). The systemic availability of nifedipine after intraduodenal administration was on the average between 52% and 57%, indicating that nifedipine is extensively metabolized during first passage through the liver. Avoidance of first-pass metabolism was investigated following buccal, rectal and percutaneous administration to rats. These nonportal routes of administration gave approximately 10-30% increases in systemic availability compared to that from intraduodenal nifedipine delivery. Moment analysis revealed variations of mixing condition of nifedipine at the dosing site. It was shown that the absorption occurs in a mammillary manner after intraduodenal and rectal administration. On the other hand, there is steady-state absorption of the drug from the buccal route of administration. Following percutaneous administration, the drug seems to be absorbed catenary to some degree.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Buccal↗
PubMed2004

Efficacy of rectal artesunate compared with parenteral quinine in initial treatment of moderately severe malaria in African children and adults: a randomised study.

BACKGROUND: Many patients with malaria of increasing severity cannot take medicines orally, and delay in injectable treatment can be fatal. We aimed to assess the reliability of absorption, antimalarial efficacy, and tolerability of a single rectal dose of artesunate in the initial management of moderately severe falciparum malaria. METHODS: 109 children and 35 adults were randomly assigned to rectal artesunate (single dose of about 10 mg/kg) or parenteral quinine treatment (10 mg/kg at 0, 4, and 12 h). The primary endpoint was the proportion of patients with peripheral asexual parasitaemia of less than 60% of that at baseline after 12 h. Secondary endpoints were clinical response and concentrations of drug in plasma. Analysis was by intention-to-treat. FINDINGS: All artesunate-treated patients had pharmacodynamic or pharmacokinetic evidence of adequate drug absorption. 80 (92%) of 87 artesunate-treated children had a 12 h parasite density lower than 60% of baseline, compared with three of 22 (14%) receiving quinine (relative risk 0.09 [95% CI 0.04-0.19]; p<0.0001). In adults, parasitaemia at 12 h was lower than 60% of baseline in 26 (96%) of 27 receiving artesunate, compared with three (38%) of eight receiving quinine (relative risk 0.06 [0.01-0.44]; p=0.0009). These differences were greater at 24 h. Clinical response was equivalent with rectal artesunate and parenteral quinine. INTERPRETATION: A single rectal dose of artesunate is associated with rapid reduction in parasite density in adults and children with moderately severe malaria, within the initial 24 h of treatment. This option is useful for initiation of treatment in patients unable to take oral medication, particularly where parenteral treatment is unavailable.

Administration, Rectal↗
PubMed1988

Vasopressin: a model for the study of effects of additives on the oral and rectal administration of peptide drugs.

We previously observed, using a relatively primitive assay, that small oral doses (on the order of 1 microgram = 1 nmol = 1000 pmol per rat) of vasopressin can produce antidiuresis in hydrated rats, and that the oral activity was enhanced by simultaneous administration of an inhibitor of intestinal proteolysis. A more sensitive semi-automated computer-linked apparatus was used to conveniently and quickly compare the antidiuretic activities of the two natural and one synthetic vasopressin peptides by several routes of administration. (The approximate dose in pmol that resulted in a 50% decrease in urine flow is indicated in square brackets.) Intravenous lysine vasopressin was used as the benchmark dose [5]. Arginine and lysine vasopressin [3500], and the synthetic analogue, 1-deamino-8-D-arginine vasopressin (DDAVP) [20], were active by oral administration. The oral activities of arginine and lysine vasopressin were always enhanced by the simultaneous administration of aprotinin [1000], a natural inhibitor of trypsin; the effect of aprotinin on the oral activity of DDAVP was inconsistent. The vasopressins were more active when administered by the rectum: arginine vasopressin [20] and DDAVP [10]. The rectal activities of the peptides were increased by the absorption adjuvant, 5-methoxysalicylate (arginine vasopressin [10]; DDAVP [0.5]). The vasopressin peptides were also delivered by mouth in an impermeable coating of an azoaromatic cross-linked polymer, which is degraded by bacteria in the colon, to release the peptides in the upper colon for absorption (lysine vasopressin [525]).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Pharmacokinetics and efficacy of rectal versus oral sustained-release morphine in cancer patients.

Sustained-release morphine (MST) given by the rectal route was compared with oral MST in an open randomised cross-over trial in ten patients with cancer who received stable doses of MST. No significant difference was found in the areas under the curve of the concentration-time profiles (AUC) following oral or rectal administration for parent morphine. The AUCs determined for morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) after oral administration were approximately twice those obtained following rectal administration. The maximal concentration achieved was lower and the time to maximal concentration was longer following rectal administration for morphine, M6G and M3G. The relative mean arrival times following rectal administration were significantly longer for morphine and M3G but not for M6G. These findings suggest slower absorption but less first-pass metabolism of MST after rectal administration. No significant difference was noted between the oral and the rectal route in measurements on visual-analogue scales for pain or side effects. We recommend the rectal route as being suitable for MST administration when the oral route is no longer available. In changing from oral to rectal administration, the same dose and dose interval may be used, but dose adjustment may be needed.

Administration, Oral↗
PubMed1992

Verapamil alters eicosanoid synthesis and accelerates healing during experimental colitis in rats.

In inflammatory bowel disease, prostaglandins are mucosal protective whereas leukotrienes are proinflammatory. Recent evidence suggests that the formation and action of leukotrienes are calcium-dependent, whereas the formation and action of prostaglandins are not. To examine the possibility that, because of differential regulation of arachidonic acid metabolism, calcium channel blockade might alter mucosal eicosanoid synthesis and accelerate healing during inflammatory bowel disease, we treated a 4% acetic acid-induced colitis model with verapamil and/or misoprostol and determined the effects on colonic macroscopic injury, mucosal inflammation as measured by myeloperoxidase activity, in vivo intestinal fluid absorption, and mucosal prostaglandin E2 and leukotriene B4 (LTB4) levels as measured by in vivo rectal dialysis. In colitic animals, verapamil treatment significantly improved colonic fluid absorption and macroscopic ulceration. This mucosal-protective effect of verapamil occurred in the presence of a twofold reduction in mucosal LTB4 synthesis. In noncolitic animals, verapamil alone had no effect on in vivo fluid absorption, macroscopic ulceration, or myeloperoxidase activity but did induce a threefold reduction in LTB4 synthesis in addition to shifting arachidonic acid metabolism towards a sixfold stimulation of prostaglandin E2 synthesis. Our results show that, when administered before the experimental induction of colitis, the calcium channel blocker, verapamil, has a mucosal-protective effect that occurs as a consequence of reduced mucosal leukotriene synthesis and increased prostaglandin synthesis. This differential regulation of arachidonic acid metabolism may play an important role in the development of novel therapeutic agents for inflammatory bowel disease.

Animals↗
PubMed1996

The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients.

Multiple doses of delta 9-tetrahydrocannabinol (THC) capsules (Marinol) and THC hemisuccinate suppositories were administered in 24-hour intervals to 2 patients with organically caused spasticity. After oral doses of 10-15 mg THC, peak plasma levels from 2.1 to 16.9 ng/ml THC and 74.5 to 244.0 ng/ml 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THC-COOH, major THC metabolite) were measured by GC/MS within 1-8 h and 2-8 h, respectively. After rectal doses of 2.5-5 mg THC, peak plasma levels from 1.1 to 4.1 ng/ml THC and 6.1 to 42.0 ng/ml THC-COOH were measured within 2-8 h and 1-8 h, respectively. The bioavailability resulting from the oral formulation was 45-53% relative to the rectal route of administration, due to a lower absorption and higher first-pass metabolism. The effect of THC on spasticity, rigidity, and pain was estimated by objective neurological tests (Ashworth scale, walking ability) and patient self-rating protocols. Oral and rectal THC reduced at a progressive stage of illness the spasticity, rigidity, and pain, resulting in improved active and passive mobility. The relative effectiveness of the oral vs. the rectal formulation was 25-50%. Physiological and psychological parameters were used to monitor psychotropic and somatic side-effects of THC. No differences in the concentration ability, mood, and function of the cardiovascular system could be observed after administration of THC.

Administration, Oral↗
PubMedDate not supplied

[Comparison of salicylazosulfapyridine bioavailability following oral and rectal administration in patients with ulcerative colitis].

Salicylazosulfapyridine--a drug commonly used in the ulcerative colitis--is effective following both oral and rectal administration. Pharmacokinetics of the drug given per rectum (in the form of suppositories) has not been investigated so far. The present study aims at comparing bioavailability of salicylazosulfapyridine following oral and rectal administration to patients with the ulcerative colitis and healthy volunteers. It was found, that following rectal administration the drug is not so readily absorbed as in oral dosage form. No sulfapyridine and 5-aminosalicylic acid have been detected in blood serum, when the drug was given in the form of rectal suppositories. Clinical stage of the disease did not affect absorption of both unchanged drug and its metabolites. Due to the fact, that the drug is active locally, rectal suppositories seem a therapeutical alternative in patients only with lesions localized in the rectum.

Administration, Oral↗