Release and absorption rates of intramuscularly and subcutaneously injected pharmaceuticals (II)

Zuidema, J.; Kadir, F.; Titulaer, H. A. C.; Oussoren, Christien

doi:10.1016/0378-5173(94)90103-1

Cited by 101 publications

(67 citation statements)

References 52 publications

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“…This values is similar to that reported for dogs (60%) (Carli et al, 1999;Chicoine et al, After multiple administration bioavailability was higher (p<0.05), this difference could be reflecting the improvement of absorption when small volumes are injected (Zuidema et al, 1994).…”

Section: Resultssupporting

confidence: 78%

Pharmacokinetics of Cephalexin after Intravenous and Single and Multiple Intramuscular Administration to Rabbit

Meneses¹,

Albarellos²,

Landoni³

2014

IJVMR

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Cephalexin is a first generation cephalosporin widely used in rabbits. Its spectrum includes Pasteurella multocida and Staphylococcus aureus. These bacteria, together with Bordetella bronchiseptica, are the main cause of respiratory infections. Although many textbooks on rabbit therapeutics report the use of cephalexin, including administration schedules, there are not published papers on the pharmacokinetics of cephalexin after IV and IM administration to rabbit. Therefore, the objective of the present study was to describe cephalexin disposition in rabbits after intravenous and single and multiple intramuscular administrations. Three administration schedules were studied: single IV administration (10 mg/kg), single IM administration (10 mg/kg) and multiple IM administration (2.5 mg/kg/6). Serial blood samples were collected over a 24 h period. Cephalexin plasma concentrations were determined by microbiological method using Kocuria rhizophila ATCC 9341 as microorganism test. No statistical differences were observed between routes of administration for any of the estimated PK parameters. The unique difference was observed on bioavailability between intramuscular administration schedules. Elimination half-life was 1.45, 1.09 and 1.91 h for the single IV, single IM and multiple IM administration, respectively. Bioavailability after single and multiple IM administration was 47 and 97.5%, respectively. After multiple IM administration maximum and minimum plasma concentration at steady state were 2.77 and 0.34 µg/ml, while Cmax after single IM administration was 9. 22 µg/ml.Considering that for betalactams the PK/PD breakpoint recommended for efficacy (T > MIC) should be 50-80% and that the reported MIC for most gram-positive organisms and Pasteurella multocida is ≤1.0 μg/ml, the present study demonstrates that a single IM dose of 10 mg/kg/24 h is enough to maintain therapeutic concentrations for a 24 hours period. When a 2.5mg/kg dose is used administration every 6 hours is recommended.

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Section: Resultssupporting

confidence: 78%

Pharmacokinetics of Cephalexin after Intravenous and Single and Multiple Intramuscular Administration to Rabbit

Meneses¹,

Albarellos²,

Landoni³

2014

IJVMR

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“…Nevertheless, the drug release and absorption might be influenced by several other factors such as the agglomeration or the local spreading of the drug particulates, the particle size, and surface properties (e.g., the host protein adsorption) that dictate the phagocytosis efficiency, the susceptibility to the local enzymatic (pro)drug degradation, and lymphatic uptake, all of which can be modulated by the local inflammatory response (Zuidema et al 1994;Medlicott, Waldron, and Foster 2004;McLennan, Porter, and Charman 2005). Hence, some challenges associated with the parenteral administration of LAIs, especially related to the complex in vivo disposition and pharmacokinetics, remain to be elucidated and are currently the subject of investigations (Darville et al 2014).…”

Section: Introductionmentioning

confidence: 99%

“…The drug absorption from LAI suspensions of practically water-insoluble drugs is generally considered to be dissolution rate limited and, therefore, driven by the physical properties of the nano-/microparticles and the depot being formed upon IM or SC injection (Zuidema et al 1994;Samtani, Vermeulen, and Stuyckens 2009). Nevertheless, the drug release and absorption might be influenced by several other factors such as the agglomeration or the local spreading of the drug particulates, the particle size, and surface properties (e.g., the host protein adsorption) that dictate the phagocytosis efficiency, the susceptibility to the local enzymatic (pro)drug degradation, and lymphatic uptake, all of which can be modulated by the local inflammatory response (Zuidema et al 1994;Medlicott, Waldron, and Foster 2004;McLennan, Porter, and Charman 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Finally, the physical behavior of the formulation (e.g., the formulation spreading within the connective tissues, particle agglomeration, etc.) also plays an important role in the in vivo drug release and absorption (Zuidema et al 1994). Since all the above processes can directly or indirectly be influenced by the acute inflammatory components, as they modulate the inflammatory cascade, it is important to consider early time points (e.g., 24 and 48 hr) for the examination of the LAI nano-/microsuspension injection sites and adapt the study design to the expected duration of the host-formulation interactions.…”

mentioning

confidence: 99%

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Modeling the Time Course of the Tissue Responses to Intramuscular Long-acting Paliperidone Palmitate Nano-/Microcrystals and Polystyrene Microspheres in the Rat

et al. 2015

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Long-acting injectable (LAI) drug suspensions consist of drug nano-/microcrystals suspended in an aqueous vehicle and enable prolonged therapeutic drug exposure up to several months. The examination of injection site reactions (ISRs) to the intramuscular (IM) injection of LAI suspensions is relevant not only from a safety perspective but also for the understanding of the pharmacokinetics. The aim of this study was to perform a multilevel temporal characterization of the local and lymphatic histopathological/ immunological alterations triggered by the IM injection of an LAI paliperidone palmitate suspension and an analog polystyrene suspension in rats and identify critical time points and parameters with regard to the host response. The ISRs showed a moderate to marked chronic granulomatous inflammation, which was mediated by multiple cyto-/chemokines, including interleukin-1b, monocyte Chemoattractant Protein-1, and vascular endothelial growth factor. Lymphatic uptake and lymph node retention of nano-/microparticles were observed, but the contribution to the drug absorption was negligible. A simple image analysis procedure and empirical model were proposed for the accurate evaluation of the depot geometry, cell infiltration, and vascularization. This study was designed as a reference for the evaluation and comparison of future LAIs and to support the mechanistic modeling of the formulation-physiology interplay regulating the drug absorption from LAIs.

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“…Sometimes, physiological factors may critically affect drug absorption because the rate and extent of intramuscular drug absorption are very erratic and variable (33,34). In this work, we evaluate the pharmacokinetic properties of octreotide from microspheres and investigate the pharmacokinetic parameters and repeated serum-drug concentrations from the point of view of the in vivo drug absorption.…”

Section: Introductionmentioning

confidence: 99%

Sustained-Release Delivery of Octreotide from Biodegradable Polymeric Microspheres

et al. 2011

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Abstract. The study reports on the drug release behavior of a potent synthetic somatostatin analogue, octreotide acetate, from biocompatible and biodegradable microspheres composed of poly-lactic-coglycolic acid (PLGA) following a single intramuscular depot injection. The serum octreotide levels of three Oakwood Laboratories formulations and one Sandostatin LAR ® formulation were compared. Three formulations of octreotide acetate-loaded PLGA microspheres were prepared by a solvent extraction and evaporation procedure using PLGA polymers with different molecular weights. The in vivo drug release study was conducted in male Sprague-Dawley rats. Blood samples were taken at predetermined time points for up to 70 days. Drug serum concentrations were quantified using a radioimmunoassay procedure consisting of radiolabeled octreotide. The three octreotide PLGA microsphere formulations and Sandostatin LAR ® all showed a two-phase drug release profile (i.e., bimodal). The peak serum drug concentration of octreotide was reached in 30 min for all formulations followed by a decline after 6 h. Following this initial burst and decline, a second-release phase occurred after 3 days. This second-release phase exhibited sustained-release behavior, as the drug serum levels were discernible between days 7 and 42. Using pharmacokinetic computer simulations, it was estimated that the steady-state octreotide serum drug levels would be predicted to fall in the range of 40-130 pg/ 10 μL and 20-100 pg/10 μL following repeat dosing of the Oakwood formulations and Sandostatin LAR ® every 28 days and every 42 days at a dose of 3 mg/rat, respectively.KEY WORDS: in vivo drug release; pharmacokinetic simulation; PLGA microspheres; polypeptide/ protein drug delivery; single depot injection.

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Release and absorption rates of intramuscularly and subcutaneously injected pharmaceuticals (II)

Cited by 101 publications

References 52 publications

Pharmacokinetics of Cephalexin after Intravenous and Single and Multiple Intramuscular Administration to Rabbit

Pharmacokinetics of Cephalexin after Intravenous and Single and Multiple Intramuscular Administration to Rabbit

Modeling the Time Course of the Tissue Responses to Intramuscular Long-acting Paliperidone Palmitate Nano-/Microcrystals and Polystyrene Microspheres in the Rat

Sustained-Release Delivery of Octreotide from Biodegradable Polymeric Microspheres

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