Bioavailability of intramuscularly administered tenoxicam

Bioavailability of intramuscularly administered tenoxicam relative to single oral and relative to intravenous doses was determined in two separate randomized crossover studies. Twelve healthy volunteers (12 males, age 20–30 years) received a rapid intravenous injection and a single intramuscular dose and 12 other subjects (11 males, 1 female, age 21–25 years) a single oral and a single intramuscular dose of 20 mg of tenoxicam on two different occasions. The wash-out period between the two consecutive treatments was 4 weeks. Plasma concentrations after dosing were determined by a specific HPLC method. Differences in tenoxicam concentration-time profiles after the different routes of administration were limited to the first 2 h after dosing. Later, plasma concentrations were almost superimposable within and across the two studies. The extent of absorption of intramuscularly administered tenoxicam was complete (mean ± CV per cent: F_abs 0.99 ± 20 per cent) with no difference between the two extravascular administrations (F_rel 0.95 ± 10 per cent, intramuscular vs oral). After intramuscular administration tenoxicam was more rapidly absorbed compared to the oral dose (T_max 0.71 h ± 80 per cent vs 1.4 h ± 62 per cent; p>0.05). Peak concentrations after oral and intramuscular administration (C_max 2.5 mg 1^?1 ± 19 per cent vs 2.7 mg l^?1 14 per cent; p <0.05) were very similar.     

Pharmacokinetics of physostigmine intramuscularly administered to guinea pigs

Physostigmine pharmacokinetics was determined in guinea pigs following im administration of 5-146 micrograms/kg. Eighteen male guinea pigs were divided into three equal groups and given dosages of 5, 27, and 146 micrograms/kg, respectively. Physostigmine was given in the right hind limb and blood samples were collected at various times up to 300 min postinjection via an indwelling carotid catheter. Unbound physostigmine plasma concentrations were analyzed by HPLC. The concentration-time profile for each animal was fitted to standard pharmacokinetic models. A one-compartment open model with first-order absorption and elimination provided the best fit. For all dosage groups, physostigmine concentrations peaked in approximately 30 min. Apparent volumes of distribution (assuming 100% bioavailability) ranged from 1.9 to 2.2 L/kg. Systemic clearances and elimination half-lives were 30-36 mL/min/kg and 40-50 min, respectively. The area under the concentration-time curve and the Cmax were linearly related to the dose, indicating pharmacokinetic linearity. In conclusion, physostigmine, intramuscularly administered to the guinea pig, is absorbed, distributed, and eliminated rapidly, and the pharmacokinetics behave linearly within the 5-146-micrograms/kg dosage range.     

Pharmacokinetics of diazepam intramuscularly administered to rhesus monkeys.

The purpose of this study was to define the pharmacokinetics of diazepam in monkeys following an im injection of 100 micrograms/kg (the minimum effective dose that prevents nerve agent-induced convulsions in pyridostigmine-pretreated, atropine- and 2-PAM-treated monkeys) in order to predict what im dose in humans is needed to prevent nerve agent-induced convulsions. Six rhesus monkeys were administered diazepam in the hind limb. Blood (3 mL) was collected via an indwelling saphenous catheter immediately prior to and 5, 10, 15, 25, 40, 60, 90, 120, 180, and 240 min after diazepam dosing. A contract laboratory, blind to the labeling code, analyzed diazepam serum concentrations by electron-capture gas chromatography and the percentage of unbound diazepam by equilibrium dialysis. The concentration-time data for total (unbound and bound) diazepam individually determined for each animal was best described by a one-compartment open model with first-order absorption and elimination. The average maximum serum concentration (50 ng/mL) was reached in 29 min. The volume of distribution and systemic clearance, assuming 100% bioavailability, were 1.5 L/kg and 19.4 mL/min/kg, respectively. The percentage of diazepam unbound to serum proteins was 4.6% and, therefore, the maximum concentration of free diazepam was 2.3 ng/mL. These results, when compared with human pharmacokinetic studies, allow a means of extrapolating effective monkey anticonvulsant doses to humans on a pharmacokinetic basis.     

Pharmacokinetics of cefoxitin administered intramuscularly to rabbits with experimentally-induced renal impairment

The pharmacokinetics of Cefoxitin were studied in rabbits with normal renal function and with varying degrees of renal impairment induced experimentally by uranyl nitrate. All animals received a single intramuscular (i.m.) dose of 40 mg kg^?1 of the antibiotic. The concentrations of Cefoxitin were determined in plasma, urine, and bile by a microbiologic plate diffusion method. The antibiotic follows a two-compartment open kinetic model. In rabbits with renal impairment there is a decrease in α, β K₁₂, K₁₂, K_a and an increase in V_d and the (AUC) with respect to the values obtained for rabbits with normal renal function. Linear relationships are established between log β and logK₁₃ and the serum creatinine. Biliary excretion of Cefoxitin is increased in states of renal impairment. A linear relationship is established between the percentage of the dose excreted in bile and the serum creatinine.     

Analgesic action and pharmacokinetics of lysine acetylsalicylate administered intramuscularly

The analgesic effect, acute toxicity and pharmacokinetics of lysine acetylsalicylate (LAS), a water-soluble salt of acetylsalicylic acid (ASA) were studied as compared with a 50% solution of analgin and a 4% solution of amidopyrine at intramuscular administration and ASA administered intragastrically. During inflammation-induced pain in rats LAS exerts a pronounced analgesic effect exceeding the activity of other agents. LD50 of LAS was similar to that of analgin and ASA. LAS toxicity was significantly less than that of amidopyrine. Bioavailability of ASA at intramuscular administration to rabbits was close to that at intravenous injection and significantly higher as compared with intragastric administration.     

Safety, tolerance, and pharmacokinetics of cefepime administered intramuscularly to healthy subjects

Steady state pharmacokinetics, absolute bioavailability, and dose proportionality of cefepime were evaluated in healthy male subjects after single (250, 500, 1000, or 2000 mg) and multiple (1000 mg every 12 hours for 10 days) intramuscular injections. Safety and tolerance were also monitored. High performance liquid chromatography/UV methodology was used to determine cefepime concentrations in plasma and urine. Key pharmacokinetic parameters were determined using noncompartmental methods. Cefepime was absorbed rapidly; mean peak times were 1.0-1.6 hours. Pharmacokinetics were linear over the 250-mg to 2000-mg dose range, with mean total body clearance ranging from 125 to 141 mL/min. The peak plasma concentration and area under the curve increased in a dose-proportional manner. The apparent elimination half-life (2 hours) did not appear to be influenced by dose or by duration of dosing. No accumulation of cefepime was observed during the multiple-dose study. More than 80% of the administered dose was excreted in the urine as unchanged cefepime, and absolute bioavailability after intramuscular dose was 100%. Cefepime was well tolerated. Most subjects experienced none to mild pain and only minimum discomfort at the site of injection.     

A pharmacokinetic model for alpha interferon administered subcutaneously

AIMS: To model the pharmacokinetic profiles of alpha interferon (alphaIFN) after a single subcutaneous (s.c.) injection of 3 million units of alpha 2b interferon, to correlate the pharmacokinetic parameters with patient demographic covariates, and to develop a limiting sampling strategy for determining the alphaIFN plasma area under the curve of concentration vs time (AUC). METHODS: The plasma alphaIFN pharmacokinetics were determined in 27 patients with chronic hepatitis C virus infection after the first s.c. injection of the drug. Ten patients had normal renal function and 17 were chronic haemodialysis patients. Plasma samples were assayed by an Elisa method. Concentration-time data was analysed by a population approach using NONMEM. RESULTS: The pharmacokinetic model which better described the concentration vs time data was a one-compartment model with two processes of absorption: a zero-order followed by a first-order process. The mean clearance of dialysis patients represented 37% (with 95% confidence interval: 30% -44%) of the mean value of the patients with normal renal function. The volume of distribution was significantly correlated to the body surface area. Bayesian analysis using NONMEM allowed determination of the individual plasma AUC from three samples within the 24 h period post s.c. injection. CONCLUSIONS: The present pharmacokinetic model will allow one to obtain individual parameters such as, the area under the curve of concentration vs time from a limited-sampling strategy, and to perform pharmacokinetic-pharmacodynamic analysis of combined alphaIFN plasma concentrations and viraemic data.     

Development and evaluation of intramuscularly administered nano/microcrystal suspension

Introduction: Formulation of nanocrystals is one of the most important drug delivery systems for poorly soluble drug molecules. Nanocrystals are produced by techniques like precipitation, media milling, high-pressure homogenization, and so on. In order to achieve sustained release and higher absorption of nanosuspensions, intramuscularly administered nanosuspensions have been developed. As well, intramuscularly administered nanosuspensions have been implemented in order to improve the bioavailability of drug nanocrystals which have both a low oral bioavailability and cannot be administered by intravenous injection routes.

Areas covered: This review summarizes studies that have focused on the production, classification, in vitro release and in vivo pharmacokinetics of intramuscularly administered nanosuspensions. In order to avoid common drawbacks of intramuscularly administered nanosuspensions, such as tissue residues and some local tissue damage, nanosuspensions with a reduced administration volume of high drug loading and extended therapeutic effects are developed.

Expert opinion: Intramuscularly administered nano/micro crystal suspensions have been developed for the treatment of various diseases such as schizophrenia, hormone disordered diseases, HIV and more. Additionally, intramuscularly administered nanosuspensions are also a good route for the development of traditional chinese medicines which have lower oral bioavailability and are not suitable for intravenous injection.     

Local effects and mechanism of absorption of iron preparations administered intramuscularly

An attempt has been made to correlate factors involved in the absorption of iron-polysaccharide complexes administered intramuscularly. Different complexes varied greatly in degree of retention in muscle and in diffusibility in agar; these two characteristics were not closely related. The local changes in the muscle produced by the iron complexes consisted of an acute inflammatory reaction at the site of injection, with degenerative changes. Subsequent regeneration was rapid and complete. The major proportion of the absorption occurred during the initial 72 hr. and appeared to be mediated partly by the inflammatory reaction evoked, with enhancement of lymphatic transport of the iron complex. Rapid fixation by tissue macrophages impeded absorption and, with some complexes, this factor may make much of the injection inaccessible.     

Pharmacokinetics of intramuscularly administered biperiden in guinea pigs challenged with soman

Biperiden is an anticholinergic compound that has demonstrated effectiveness for treating organophosphate-induced seizure/convulsions. The plasma levels of biperiden associated with this efficacy have not yet been defined. In this study, the pharmacokinetics and tissue distribution of biperiden after intramuscular administration of 0.5 mg/kg were conducted while monitoring pharmacodynamic (electroencephalographic) data in soman-exposed guinea pigs. Overall, 59% of the animals had seizures terminated within 30 min of the biperiden administration. The mean time to seizure termination was 15.9 min. The pharmacokinetics of biperiden after i.m. administration to guinea pigs were best described by a one-compartment model with first-order absorption and elimination. The maximal plasma biperiden concentration (34.4 ng/mL) in seizure-terminated animals occurred at 26.3 min. Extensive partitioning into peripheral tissues was noted supporting the relatively large volume of distribution observed. Maximal biperiden concentrations in the cortex and brain stem were found at 30 min and were 2.3 and 1.7 times greater, respectively, than that in plasma. The time for maximal plasma concentration was found to corresponded well with the mean time to seizure termination following drug administration.     

Cross-over study of the pharmacokinetics of cefonicid administered intravenously or intramuscularly to healthy adult humans

The pharmacokinetics of cefonicid were investigated in eight healthy adults. A one-gram dose was administered either intramuscularly or intravenously in a cross-over design study. Mean peak cefonicid plasma concentrations of 186 to 204 mcg/ml and 88 to 123 mcg/ml were achieved after intravenous and intramuscular injection, respectively, with elimination half-lives of 4.9 h and 5.3 h. Cefonicid concentrations were measured by both microbiological (M.A.) and high-performance liquid chromatography (HPLC) assays. Results were quite similar with the two techniques, except for the urinary recovery of cefonicid in the first 24 hours (83% of the dose with MA - vs 53% with HPLC method). The apparent volume of distribution (Vd area) was 0.18 1/kg; the total body clearance (CT) and the renal clearance (CR) were 24-26 ml/min and 15-19 ml/min, respectively. The kinetic data of cefonicid were not significantly different for the two routes of administration. A one-gram i.v. or i.m. cefonicid dose produced high and prolonged plasma concentrations with a longer half-life than obtained with commonly used cephalosporins.     

Population pharmacokinetic investigation of actinomycin-D in children and young adults

Actinomycin-D is an antineoplastic agent that inhibits RNA synthesis by binding to guanine residues and inhibiting DNA-dependent RNA polymerase. Although actinomycin-D has been used to treat rhabdomyosarcoma and Wilms tumor for more than 40 years, the dose/exposure relationship is not well characterized. The objective of this study was to develop an initial population pharmacokinetic model to describe actinomycin-D disposition in children and young adults from which a prospective study could be designed. A total of 165 actinomycin-D plasma concentration measurements from 33 patients, aged 1.6 to 20.3 years, were used for the analysis. The data were analyzed using nonlinear mixed-effects modeling with the NONMEM software system. Age, weight, and gender were examined as covariates for the ability to explain interindividual variability in actinomycin-D pharmacokinetics. The final model was qualified via predictive check and nonparametric bootstrap procedures. A 3-compartment model with first-order elimination was chosen as the structural model. Allometric expressions incorporating weight were used to describe the effects of body size on actinomycin-D pharmacokinetics. Age and gender had no discernible effects on actinomycin-D pharmacokinetics in the population studied. The predictive check showed that the developed model was able to simulate data in close agreement with the actual study observations. The availability of an initial population pharmacokinetic model to describe actinomycin-D pharmacokinetics will facilitate the development of a large-scale clinical trial to study the actinomycin-D dose/exposure relationship in pediatric patients with rhabdomyosarcoma and Wilms tumor. The covariate analysis described by the current data set suggests that indices of body size captured via allometric expressions improve the partition of variation in actinomycin-D pharmacokinetics from this pilot data set. Relationships between pharmacokinetics and toxicity will be examined in future prospective studies in which children less than 1 year old will be enrolled.     

Placental and blood-CSF transfer of intramuscularly administered atropine in the same person

Both placental and blood-CSF transfer of atropine (0.01 mg/kg intramuscularly) was measured (by RIA) in 11 parturients undergoing Caesarean section under spinal analgesia. In the foeto-placental unit a significant penetration into amniotic fluid was found, whereas in CSF there was a measurable level of the drug (greater than 1.5 ng/ml) in only one mother. Our results show that there is a fundamental difference in the penetrability of tertiary ammonium alkaloids like atropine through these two biological membranes. However, our results concern penetration into human lumbar CSF and do not necessarily reflect potential penetration into the ventricular CSF, choroid plexus or brain ventricular ependyma.     

Absorption of intramuscularly administered [14C]haloperidol decanoate in rats

When [14C]haloperidol decanoate, an ester of haloperidol and decanoic acid, was given intramuscularly to rats, levels of total radioactivity and haloperidol decanoate in medial iliac and hypogastric sacral lymph nodes nearest to injection sites were the highest in examined lymph nodes and plasma. These lymph node levels became maximum 16 days after administration and declined gradually with half-life (around 14 days) similar to those of plasma total radioactivity, haloperidol decanoate and haloperidol. However, when the labelled ester was given intravenously, plasma total radioactivity disappeared far more rapidly. Much more radioactivity was found in hind limbs whose femoral muscles had been injected than in other body parts, even at late stages after administration. Haloperidol alone was found in the brain after [14C]haloperidol decanoate was given either intramuscularly or intravenously. It was concluded that haloperidol decanoate injected in rat femoral muscle was rate-limitedly distributed in lymph circulation and that the absorbed ester did not penetrate the brain through the blood-brain barrier but formed haloperidol did.     

A phase I and pharmacokinetic study of LAF389 administered to patients with advanced cancer

LAF389 is a synthetic analogue of bengamide B, a natural product isolated from Jaspidae sponges. LAF389 has both antiproliferative and antiangiogenetic properties, and preclinical investigations showed a broad antitumour activity. This clinical trial aimed to determine the safety and pharmacokinetic profile of LAF389 administered as a slow intravenous injection for 3 consecutive days every 3 weeks in patients with advanced solid tumours. Eight dose levels were tested: 1, 2.5, 5, 10, 15, 30, 25 and 20 mg/day. A total of 33 patients, median age 52 years (range 33-72), with refractory solid tumours were enroled, 19 men and 14 women with a median World Health Organization performance status of 1 (0-4). Seventy-eight cycles of treatment have been administered (mean 2.5, range 1-10). Four cardiovascular dose-limiting toxicities were reported at 30 mg (2/2 patients) and 25 mg (2/9 patients), eight additional patients at various dose levels had (cardio)vascular toxicity, probably drug related, and one patient died owing to pulmonary embolism at the 5 mg dose. No objective responses were recorded. Pharmacokinetic parameters were variable, although linear and without obvious accumulation from cycle I to cycle II. LAF389 dose escalation was terminated owing to occurrence of unpredictable cardiovascular events. This, associated with the lack of clinical activity, did not warrant further investigation of this agent.     

Transfer profile of intramuscularly administered tetrodotoxin to non-toxic cultured specimens of the pufferfish Takifugu rubripes

Tetrodotoxin (TTX) was intramuscularly administered to non-toxic cultured specimens of the pufferfish Takifugu rubripes to investigate TTX transfer/accumulation profiles in the pufferfish body. In two groups of test fish administered either 50 MU/individual of TTX standard (purified TTX; PTTX) or crude extract of toxic pufferfish ovary (crude TTX; CTTX), TTX rapidly transferred from the muscle via the blood to other organs. The toxin transfer profiles differed between groups, however, from 4 to 72 h. In the PTTX group, little TTX was retained in the liver, and most (>96%) of the toxin remaining in the body transferred/accumulated in the skin after 12 h, whereas in the CTTX group, a considerable amount of toxin (15%-23% of the administered toxin or 28%-58% of the remaining toxin) was transferred/retained in the liver for up to 24 h, despite the fact that 89% of the remaining toxin transferred/accumulated in the skin at the end of rearing period (168 h). The total amount of toxin remaining in the entire body at 1-4 h was approximately 60% of the administered toxin in both groups, which decreased at 8-12 h, and then increased again to approximately 60%-80% at 24-168 h. Immunohistochemical observation revealed that the toxin accumulated in the skin was localized at the basal cells of the epidermal layer.     

Effect of lidocaine on the absorption,disposition and tolerance of intramuscularly administered cefoxitin

Summary The use of lidocaine HCl solution at concentrations of 0.5 and 1.0% to reconstitute sodium cefoxitin relieves the pain associated with intramuscular injections of the antibiotic. Cefoxitin absorption by the intramuscular route is initially rapid and is virtually complete. Peak serum concentrations, corresponding to about one-half those of a comparable intravenous infusion, are achieved in 30 min. Continuing absorption tends to maintain higher serum concentrations for longer times. Renal clearance and serum half-life of cefoxitin do not appear to be affected by lidocaine at its effective anaesthetic concentrations.     

Transfer profile of intramuscularly administered tetrodotoxin to artificial hybrid specimens of pufferfish, Takifugu rubripes and Takifugu niphobles

Tetrodotoxin (TTX) was intramuscularly administered to artificially hybridized specimens of the pufferfish Takifugu rubripes and Takifugu niphobles to investigate toxin accumulation in hybrids, and TTX transfer/accumulation profiles in the pufferfish body. In the test fish administered 146 MU TTX in physiologic saline, TTX rapidly transferred from the muscle via the blood to other organs. Toxin transfer to the ovary rapidly increased to 53.5 MU/g tissue at the end of the 72-h test period. The TTX content in the liver and skin was, at most, around 4-6 MU/g tissue, and in the testis it was less than 0.01 MU/g tissue. On the other hand, based on the total amount of toxin per individual (% of the administered toxin), the skin and the liver contained higher amounts (20-54% and 2-24%, respectively), but the amount in the liver rapidly decreased after 8-12 h, and fell below the level in the ovary after 48 h. These findings suggest that part of the TTX is first taken up in the liver and then transferred/accumulated in the skin in male specimens and in the ovary in female specimens.