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Globally, people 65 years of age and older are the fastest growing segment of the population. Physiological manifestations of the aging process include undesirable changes in body composition, declines in cardiorespiratory fitness, and reductions in skeletal muscle size and function (i.e., sarcopenia) that are independently associated with mortality. Decrements in muscle protein synthetic responses to anabolic stimuli (i.e., anabolic resistance), such as protein feeding or physical activity, are highly characteristic of the aging skeletal muscle phenotype and play a fundamental role in the development of sarcopenia. A more definitive understanding of the mechanisms underlying this age-associated reduction in anabolic responsiveness will help to guide promyogenic and function promoting therapies. Recent studies have provided evidence in support of a bidirectional gut-muscle axis with implications for aging muscle health. This review will examine how age-related changes in gut microbiota composition may impact anabolic response to protein feeding through adverse changes in protein digestion and amino acid absorption, circulating amino acid availability, anabolic hormone production and responsiveness, and intramuscular anabolic signaling. We conclude by reviewing literature describing lifestyle habits suspected to contribute to age-related changes in the microbiome with the goal of identifying evidence-informed strategies to preserve microbial homeostasis, anabolic sensitivity, and skeletal muscle with advancing age.

Identification and evaluation of long-term markers is crucial in prolonging the detection window for anabolic steroid abuse in sport. Recently, sulfoconjugated epiandrosterone was identified as a potential long-term marker for the abuse of certain endogenous anabolic agents, including testosterone, which continues to be widely used as a performance enhancing agent in sport. To evaluate the applicability of epiandrosterone sulfate as a marker for testosterone use, administration studies were conducted with multiple modes of testosterone administration - transdermal, intramuscular, and subcutaneous. A modified sample preparation method was used to collect both glucuronidated and sulfoconjugated analytes of interest. Carbon isotope ratio measurements from the administration studies are presented here. Epiandrosterone was less effective than the conventionally used target compounds for detection of the low dose application (transdermal gel). With intramuscular administration, epiandrosterone was more diagnostic than with transdermal administration, but it did not prolong the detection window more than the conventional target compounds. With subcutaneous administration, the doses administered to the subjects were varied and the effect on the epiandrosterone values was dependent on the magnitude of the dose administered. Epiandrosterone does not appear to be a useful marker in the detection of low dose testosterone administration. It is responsive to higher dose administration, but it does not provide an extension of the detection window relative to conventional target compounds.

Ketamine is a glutamate N-methyl-D-aspartate receptor antagonist that is a rapid acting dissociative anesthetic. It has been proposed to be an adjuvant treatment along with other drugs (atropine, midazolam, pralidoxime) used in the current standard of care (SOC) for organophosphate and nerve agent exposures. Ketamine is a pharmaceutical agent that is readily available to most clinicians in emergency departments and possesses a broad therapeutic index with well characterized effects in humans. The objective of this study was to determine the pharmacokinetic profile of ketamine and its active metabolite, norketamine, in F344 rats following single or repeated intramuscular administrations of subanesthetic levels (7.5 mg/kg or 30 mg/kg) of ketamine with or without the standard of care. Following administration, plasma and brain tissues were collected and analyzed using a liquid chromatography-mass spectrometry method to quantitate ketamine and norketamine. Following sample analysis, the pharmacokinetics were determined using non-compartmental analysis. The addition of the current SOC had a minimal impact on the pharmacokinetics of ketamine following intramuscular administration and repeated dosing at 7.5 mg/kg every 90 min allows for sustained plasma concentrations above 100 ng/mL. The pharmacokinetics of ketamine with and without the SOC in rats supports further investigation of the efficacy of ketamine co-administration with the SOC following nerve agent exposure in animal models.

The objectives of this study were to define disposition and systemic availability of florfenicol in alpacas. Administration of 20 mg/kg doses to 8 male alpacas by i.v., i.m. and s.c. routes was performed by randomized, 3-way crossover design. Clearance and steady state volumes (Vdss) after i.v. injection were 5 ml/min/kg and 775 ml/kg respectively. Mean residence time (MRT) and terminal phase half-life (T1/2λz) were 2.8 h and 2 h respectively. Maximum serum concentrations (Cmax) after i.m. were higher than s.c. administration (p = 0.034). After s.c. dosing, T1/2λz and MRT were greater than after i.m. injection (p 0.001; p = 0.006 respectively). Mean absorption time (MAT) after s.c. dosing was also prolonged (p = 0.006). Fractional absorption of florfenicol after i.m. and s.c. was not different (p 0.05). Serum florfenicol concentrations remained1.0 µg/ml for 20 h after i.m. dosing. Differences in rate and extent of florfenicol absorption after extravascular dosing could influence therapeutic outcomes.

Sustained release of lipophilic compounds can be achieved with oil depots. These parenteral formulations are generally injected in the vastus lateralis and deltoid muscle. It is known that the absorption rate differs between these two muscles. The reason for this is not fully understood. The aim of the current study was to investigate the fate of an oil depot in different tissues to elucidate whether the disappearance rate of oil is the cause of observed differences in absorption rate. A study with healthy volunteers was conducted to determine 1.0 mL oil depots in the vastus lateralis and deltoid muscle for two weeks. The spatial distribution of the oil depots was determined using MRI. Additionally, a study in rats was conducted to microscopically examine the oil immediately and after 31 days of injection. All rats were injected with a 0.1 mL oil depot with and without benzyl alcohol (BOH), a commonly used excipient in oil depots. In humans, it was shown that all oil depots were equal in volume and surface area directly after injection. Moreover, the disappearance rate for all oil depots was similar; within one week there was no depot visible anymore by MRI. This in contrast to the depots in rats, which were still microscopically visible after 31 days. It is concluded from these observations that the oil is dispersed to small droplets in the course of time. The resulting increase in surface area does not lead to an increase in absorption rate however. The results of this paper show that the variation in drug absorption as found for the two muscles is not caused by a distinction in surface areas or disappearance rates of the oil depots. Therefore, it is argued that the local tissue drainage (e.g. lymph flow) plays a considerable role in drug absorption from oil depots, whereby the lymph flow differs between the muscles.

Dopamine agonists have been associated with an increased risk of developing impulse control disorders (ICDs). The US Food and Drug Administration (FDA) issued a safety warning in 2016 of a possible association between ICDs and aripiprazole. Recently, one large epidemiological study has confirmed this risk. In the present study, we aim to determine whether the safety signal of ICDs associated with aripiprazole detected by the FDA is replicated in the European pharmacovigilance database (EudraVigilance). We searched for all suspected spontaneous cases of ICDs associated with aripiprazole in EudraVigilance up to 23 February 2017. To assess the association between ICD cases and each dopamine agonist drug, we calculated the proportional reporting ratios (PRRs). Among 4 905 110 events of all types recorded in EudraVigilance, we found 160 cases of ICDs associated with aripiprazole. Aripiprazole fulfilled the criteria to generate a safety signal; PRR (95% confidence interval): 16.39 (13.97-19.24). Notably, the association seemed the strongest for the depot formulation of aripiprazole; PRR (95% confidence interval): 27.13 (17.22-42.75). Our analysis of the data contained in EudraVigilance confirms the safety signal detected last year by the FDA. Interestingly, for the first time, we show that the association seems the strongest for the intramuscular depot formulation of aripiprazole.

The lethal toxicity values (log 1/LD(50)) of 527 aliphatic and aromatic compounds in oral, intravenous, intramuscular and intraperitoneal routes were used to investigate the relationships of log 1/LD(50) from different exposure routes. Regression analysis shows that the log 1/LD(50) values are well correlated between intravenous and intraperitoneal or intramuscular injections. However, the correlations between oral and intravenous or intraperitoneal routes are relatively poor. Comparison of the average residuals indicates that intravenous injection is the most sensitive exposure route and oral administration is the least sensitive exposure route. This is attributed to the difference in kinetic process of toxicity testing. The toxic effect of a chemical can be similar or significantly different between exposure routes, depending on the absorption rates of chemicals into blood. Inclusion of hydrophobic parameter and fractions of ionic forms can improve the correlations between intravenous and intraperitoneal or oral routes, but not between intraperitoneal and oral routes. This is due to the differences of absorption rate in different exposure environments from different routes. Several factors, such as experimental uncertainty, metabolism and toxic kinetics, can affect the correlations between intravenous and intraperitoneal or oral routes.

Olanzapine long-acting injection (OLAI) is a sustained-release depot antipsychotic for the treatment of schizophrenia in adults. Our objective was to explain the pharmacokinetics of OLAI to provide clinical insight. Simulation models and data from clinical trials are presented. Olanzapine concentrations were observed immediately upon injection. Half-life was ∼30 days, controlled by the slow rate of intramuscular absorption rather than the 30-h elimination rate-based half-life of oral olanzapine. As each injection builds on the drug still being released from previous injections, concentrations increase gradually until a steady state is reached after ∼3 months. Concentrations were similar to oral olanzapine and proportional to the dose; the average steady-state concentrations (10th-90th percentile) for the 150, 210, and 300 mg/2-week doses were 16-32, 15-55, and 20-67 ng/ml, respectively, and those for the 300 and 405 mg/4-week doses were 19-48 and 19-62 ng/ml, respectively. Peak concentrations most often occurred at 2-4 days after injection. Peak-to-trough fluctuation was greater for the 4-week dosing interval than the 2-week one, with no apparent clinical ramifications for these differences. Trough concentrations were above the lower end of the therapeutic range, even at the first injection. Long-term use up to 6 years indicated no additional accumulation. The impact of smoking and sex was similar, but less pronounced than for oral olanzapine.

1. The pharmacokinetics and bioavailability of levofloxacin in turkeys were investigated after a single intravenous (IV), intramuscular (IM) and oral (PO) administration of 10 mg/kg body weight. 2. The concentrations of levofloxacin in plasma samples were assayed using a microbiological assay method and pharmacokinetic parameters were calculated by non-compartmental analysis. 3. Following IV administration, the elimination half-life (t0.5(β)), volume of distribution at steady state (Vdss) and total body clearance (Cl) were 4.49 h, 1.31 l/kg and 0.23 l/h/kg, respectively. 4. After single IM and PO administrations at the same dose, levofloxacin was rapidly absorbed as indicated by an absorption half-life (t0.5ab) of 1.02 and 0.76 h, respectively; maximum plasma concentrations (Cmax) of 5.59 and 5.15 μg/ml were obtained at a maximum time (Tmax) of 2 h for both routes and levofloxacin bioavailability (F) was 96.5 h and 79.9% respectively after IM and PO administration. In vitro plasma protein binding of levofloxacin was 24.3%. 5. Based on these pharmacokinetic parameters, a dose of 10 mg/kg body weight given intramuscularly or orally every 24 h in turkeys can maintain effective plasma concentrations with bacterial infections with (minimum inhibitory concentration) MIC90 > 0.1 μg/ml.

Effect of potassium ion on the intramuscular absorption of some drugs has been examined using the rat thigh muscle clearance method. In the presence of K+ (

Oily solutions of various kind of drugs were injected into the hind leg of rats and the intramuscular absorption was investigated by the local clearance method. The intramuscular absorption of drugs having moderate lipid solubility was more rapid than that of the oily solvent itself and proceeded by the apparent first-order process. Apparent absorption rate constants were affected mainly by injection volume and by the physicochemical properties of drugs and oily solvents. The kinetic results are also consistent with a postulate that the drug was mainly absorbed after being transferred from the oily phase to the aqueous phase, and a fairly good correlationship between partition coefficient and the apparent absorption rate constant was obtained. In the case of drugs having extremely high partition coefficient, the absorption rates were very slow, for which the solubility of the drugs in the tissue fluid appeared to be a critical factor.

The kinetics of the absorption and elimination of pralidoxime chloride were investigated in the dog. Similar apparent elimination rate constants were obtained after intravenous, intramuscular, and oral administration. Although oral absorption occurred slowly, intramuscular absorption proceeded rapidly. With in situ techniques, it was found that no absorption occurred from the isolated stomach and duodenum but that absorption did take place from the jejunum and ileum.

The kinetics of ergotamine has been investigated in migrainous patients using a new, specific, sensitive HPLC assay (detection limit 100 pg/ml plasma). 10 patients were given ergotamine tartrate 0.5 mg i.v. and 5 of them received the same dose i.m. 2-3 weeks later. Blood samples were collected for up to 54 h following administration and the plasma concentration were analysed. After intravenous administration the plasma ergotamine declined rapidly, with and initial distribution half-life of 3 min followed by a mean terminal half-life of 1.86 h (range 90-155 min). The mean total plasma clearance was 11.0 ml kg-1 min-1, and the volume of distribution (Vd beta) was 1847.6 ml kg-1. Individual t1/2 beta showed a positive linear correlation with the individual Vd beta. The intramuscular absorption of ergotamine was rapid and maximum plasma levels were usually obtained 10 min following administration. The biological availability was incomplete and variable at 46.6% (range 28.3-60.8%).

The effects of the polysorbates on the intramuscular absorption of water-soluble, micelle-free drugs were investigated in the rat. The presence of a low concentration of the polysorbates caused a pronounced decrease in the absorption rates of drugs, and the reduction was reflected in their plasma levels. Absorption rates of a drug in the muscle were dependent on the concentration rather than on the absolute amount of the surfactant. The delayed clearance seemed to be operative in various drugs and was caused by the polysorbates per se—not by the hydrolysis products.

An attempt was made to use liposomes as a carrier intended for prolonged intramuscular absorption of highly water-soluble drugs. 131I-Insulin, 14C-sucrose, 14C-inulin, and 14C-cefazolin sodium, a new derivative of cepharosporin antibiotics, were chosen as model compounds. These model drugs were dissolved in pH 7.0 buffer solution and entrapped in liposomes composed of various ratios of phosphatidyl choline, cholesterol, and dicetylphosphate. After injection in the form of such liposomal suspensions, clearance of model drugs from the intramuscular injection site was delayed to a considerable extent in comparison with the control aqueous buffer injections. It was observed that the larger the amount of cholesterol incorporation into liposomes were, the slower the drug absorption became. Although the intramuscular absorption of the drugs from the rat thigh muscle was delayed by their entrapment in liposomes, extent of the prolongation was less than that expected from their in vitro release characteristics determined by dialysis experiments. Physical stability of liposomes containing 14C-cefazolin sodium was tested in the presence of serum and muscle homogenate. It appears that liposomes are gradually hydrolysed or affected by serum thereby losing their integrity and releasing the entrapped drugs.

The mechanism of the inhibition caused by polysorbate 80 on the intramuscular absorption of water-soluble drugs was studied. It was found that the absorption pattern of isonicotinamide was different from that of polysorbate 80. The inhibition of the absorption requires the existence of polysorbate 80 at the site of injection. Histological studies showed that there is no correlation between the inhibition in absorption and the local effect of polysorbate 80 which was found to cause some inflammation at the site of injection. The influence of polysorbate 80 on the capillary permeability was investigated. This was done by intravenous pre-administration of polysorbate 80, sympatholytic agent or conjugated estrogen. No difference in the intramuscular absorption of the tested drugs in the presence or absence of polysorbate 80, whether the animals were pretreated or not, could be demonstrated. Therefore, the inhibition in the intramuscular absorption of these drugs could not be attributed to a direct nor indirect effect of polysorbate 80 on the capillary walls. It was suggested that the permeation of drug through the intercellular spaces of muscle fibers and connective tissues is the more dominant process.

The rates of absorption of a variety of compounds from the tibialis anterior muscle of the rat were determined. The substances studied were aqueous solutions of isotopically labeled benzylpenicillin, hexamethonium, glucose, ouabain, urea and water. The disappearance of the radioactivity from muscle was found to be exponential with time and to be described by a single rate constant. The rates were very similar and averaged 0.159/min. The absorption rates of the various substances (molecular weights 20–585) did not appear to vary with their diffusion coefficients but were affected by vasoactive substances. The results suggest that blood flow rather than diffusion is the rate limiting step for absorption from muscle.

The effect of ethanol on the intramuscular absorption of water-soluble drugs from the rat thigh muscle was investigated. The presence of ethanol caused a pronounced decrease in the absorption rate of drugs, and the reduction was reflected by the decrease in plasma concentrations. It was also found that the absorption rate of drugs from the site of injection depends mainly on the concentration rather than the absolute amount of ethanol. A direct relationship between the relative viscosity of the injectable solution and the inhibitory absorption was demonstrated at lower concentrations of ethanol, but not at higher concentration. This shows that the inhibitory absorption effect of ethanol cannot be adequately explained by simple physicochemical factors, such as viscosity, but the existence of other factors must be acting. A constant intravenous infusion of ethanol showed no effect on the intramuscular absorption of drug. Furthermore, ethanol did not significantly change the permeability of the isolated mesentery to drug molecules. On the other hand, the connective tissue permeability was significantly decreased by the presence of ethanol and had a good correlation to the inhibitory effect of ethanol on the intramuscular absorption of drugs. From these observations, it can be concluded that the mechanism of the inhibitory effect of ethanol is mainly due to its influence on the extracellular spaces and the connective tissues permeability.

Six male and six female volunteers each received a single intramuscular injection of cephradine, a new cephalosporin antibiotic, once weekly for 3 consecutive weeks. The drug was injected into the gluteus maximus, vastus lateralis, or deltoid muscle groups. Injection sites were rotated each week so that each subject received an injection into each muscle. Pharmacokinetic evaluation of serum concentrations and urinary excretion data indicated a sex difference with respect to the rate and extent of cephradine absorption from the three injection sites. Smaller areas under the curve and absorption rate constants were observed for females after injection into each muscle group. The most striking difference was observed when cephradine was injected into the gluteus maximus muscle, where the exponential function describing the alpha phase was observed to be 1.16 +/- 0.17 hr(-1) for females and 2.70 +/- 0.34 hr(-1) for males. Total area under the mean serum concentration-time curves, mean time to peak, and peak height parameters consistent with the slower rate of absorption and lesser bioavailability in females were observed. These results show that the vastus lateralis or deltoid muscle groups are preferable to the gluteus maximus as injection sites because of the more rapid rates of drug absorption from those muscles.

The absorption characteristics and kinetics of practically water-insoluble drugs following intramuscular injection of their aqueous suspensions were investigated by the local clearance method in the m. gastrocnemius of the rat. The plot of the cube root of the residual fraction of the drug in the injection site versus time gave a good straight line. Between the absorption rate constant (j) and the initial drug concentration (C0) or injection volume (V0), the relationship jvC0g V0h was observed experimentally (g=-0.55 and h=-0.32). Comparison of j values among various compounds having different solubilities in saline (Cs') but similar colloidal properties (particle size distribution and sedimentation volume) showed that a plot of log j against log Cs'gave a linear relationship with a slope close to 0.5. The absorption rate constant (j) increased with decreasing particle size on condition that the other colloidal properties changed little. This increase was remarkable in the region of mean particle diameter (Dss) less than 2-3 μm, while it was gradual or slight in the region above this. The results could be explained by a kinetic model in which the dissolution (diffusion) process from the particle agglomerate formed by injection was assumed to be a rate-limiting step for the drug absorption. The effect of the type or concentration of the macromolecular dispersing agent was also examined in detail.

The intramuscular absorption characteristics and kinetics of practically water-insoluble drugs, which were solubilized in water with nonionic surfactants, were studied by the local clearance method in the m. gastrocnemius of the intact rat. The solubilized drugs were absorbed approximately according to 1st order kinetics. Their absorption rates were controlled by the distribution coefficient (K, micellar phase/water phase) as well as the injection volume (V0) and the surfactant concentration (Cs0), but depended little on the vehicle viscosity under the present experimental conditions. A model, based on the assumptions that the drug is distributed instantaneously between the micellar and water phases in the depot and that the drug molecules in both phases are transported into the vascular systems by diffusion at different rates, was proposed to account for the kinetic features of the process. It predicted that the plot of the 1st order absorption rate constant (k) against 1/Cso or 1/K would be approximately linear when the injection volume was fixed, the surfactant absorption was very slow, and the contribution of the drug entrapped in micelles to the absorption was much smaller than that of the free drug. The experimental results agreed well with these predictions, except for the systems of very high surfactant concentration. Experimentally, k was inversely proportional to V01/3 and this was explained reasonably by the model.

The Loo-Riegelman method was applied to serum amikacin level data after intravenous and intramuscular administration. Intramuscular amikacin absorption can be described by first-order kinetics, but the absorption rate constant decreased from 1.95 hr-1 at a 125-mg dose to 1.00 hr-1 at a 750-mg dose. This rate change apparently is a physical phenomenon due to differing dosing volumes at different doses and attendant changes in the surface area to volume ratio at the injection site. Amikacin absorption rates on intramuscular injection can be maximized by giving several smaller injections rather than a single larger injection. This phenomenon should be generally observed with aminoglycoside antibiotics and could be partly responsible for reported variations in the absorption rate and the poor predictability of serum concentrations.

This investigation was undertaken to evaluate the differences of intramuscular absorption rates of practically water-insoluble drugs in rats among the three basic dosage forms : oily solutions (including oily suspensions), aqueous suspensions, and aqueous solutions containing nonionic surfactants as solubilizers. A review of previous studies indicated that the rank order of magnitude of the absorption rates among such dosage forms was not fixed, but varied remarkably depending on the drug, the oily solvent, the surfactant and its concentration, and colloidal properties such as particle size, etc., in addition to the initial drug concentration and injection volume. Thus, we sought to establish a method for predicting the relative absorption rates from the three dosage forms empirically. The feasibility of the proposed approach was confirmed experimentally with testosterone for the three dosage forms injected intramuscularly into intact rats. In conclusion, this approach is expected to provide a novel and useful guide not only for predicting the relative absorption rates from various dosage forms but also for selecting optimal preparations for more detailed screening and preclinical testing in laboratory animals of new drugs under development.

The absorption characteristics and kinetics of practically water-insoluble drugs following subcutaneous injection of their aqueous suspensions were investigated in intact rats by the local clearance method and compared with those following intramuscular injection reported previously. The plot of the cube root of the residual fraction of the drug in the injection site versus time gave a good linear relationship under various experimental conditions. The absorption rate constant (j) increased with decreasing particle size. This increase was remarkable in the region of mean particle diameter less than 2-3 micrometers, while it was gradual or slight in the region above this. This phenomenon was explained by the fact that the in vivo spreading of particles of more than approximately 3 micrometers was still more limited by the network of the fibrous tissues. Between j and the initial drug concentration (C0) or injection volume (V0), the practically important relationship j alpha C0g V0h (g = -0.66 and h = -0.32) could approximately be derived from the experimental results. Comparison of j values among various compounds with different solubility (C's) in saline but with similar colloidal properties (particle size distribution and sedimentation volume) showed that a log j versus log C's plot gave a nearly straight line with a slope of approximately 0.5. All the results observed for the subcutaneous absorption were similar to those for intramuscular absorption and could reasonably be explained by the kinetic model proposed for intramuscular absorption.

The absorption behavior following intramuscular injection of practically waterinsoluble drugs in water-immiscible oil solution was investigated with several azo dyes and two steroids as model drugs by the local clearance method in the m. gastrocnemius of the rat. The absorption of the drug component obeyed approximately 1st order kinetics, while the absorption of the oily solvent was very slow. The injection volume (V0) influenced the absorption rate constant (k) and the correlation kv V0m was experimentally observed (for intact rats, m=-0.14 ; for anesthetized rats, m=-0.32). This was also the case at another injection site, the m. rectus femoris in rats. Comparison of the absorption rate of a drug in various oil vehicles showed that k was controlled predominantly by the oil/water distribution coefficient (K) and depended little on the viscosity of the vehicle. These results suggested that the release process of the drug component from the oily depot to the aqueous phase around it was the main route for absorption, and that the subsequent transport process in the aqueous phase might be rate-limiting. A plot of log k versus log K gave a straight line with a slope close to -1, but of a slightly smaller absolute value. This plot could be applied satisfactorily for estimating the absorption rate of other drug-oil systems. A guideline for predicting the absorption rate of a drug in oily suspension from the k value for its solution is presented.