Intramuscular drug transport under mechanical loading: Resonance between tissue function and uptake

Abstract

Dynamic architecture and motion in mechanically active target tissues can influence the pharmacokinetics of locally delivered agents. Drug transport in skeletal muscle under controlled mechanical loads was investigated. Static (0-20%) and cyclic (±2.5% amplitude, 0-20% mean, 1-3 Hz) strains and electrically paced isometric contractions (0.1-3 Hz, 0% strain) were applied to rat soleus incubated in 1 mM 20 kDa FITC-dextran. Dextran penetration, tissue porosity, and active force-length relationship over 0-20% strain correlated (r = 0.9-1.0), and all increased 1.5-fold from baseline at 0% to a maximum at 10% (L o ), demonstrating biologic significance of L o and impact of fiber size and distribution on function and pharmacokinetics. Overall penetration decreased but relative enhancement of penetration at L o increased with dextran size (4-150 kDa). Penetration increased linearly (0.084 mm/Hz) with cyclic stretch, demonstrating dispersion. Penetration increased with contraction rate by 1.5-fold from baseline to a maximum at 0.5 Hz, revealing architectural modulation of dispersion. Impact of architecture and dispersion on intramuscular transport was computationally modeled. Mechanical architecture and function underlie intramuscular pharmacokinetics and act in concert to effect resonance between optimal physiologic performance and drug uptake. Therapeutic management of characteristic function in tissue targets may enable a physiologic mechanism for controlled drug transport.

East-West pathology agreement on precancerous liver lesions and early hepatocellular carcinoma

“…infusion is interesting in confirming superior uptake; that there is little drug in the inferior wall is intriguing. These latter findings suggest that deposition of drug within myocardium is dominated by forces far beyond passive diffusion and may point to active modes of elimination consistent with observations related to contractile‐dependent drug uptake 26,27. Local delivery is then far more powerful than a dose‐limiting mode of administration and has the potential to add to the potency of clinical pharmacotherapy despite the complexity of resulting pharmacokinetics.…”

Intramuscular Administration of Paliperidone Palmitate Extended-Release Injectable Microsuspension Induces a Subclinical Inflammatory Reaction Modulating the Pharmacokinetics in Rats

“…This can be explained by the rapid effusion of the aqueous vehicle, the subsequent creation of the granulomatous envelope, and the low diffusional mobility of micrometersized particles through the continuous network of peri-and endomysial collagen fibers and narrow aqueous channels. 19,20 The formulation spreading and therefore the surface area for systemic absorption is determined by the balance between many variables including the injection volume, the rheological properties of the system, the particle size, stabilizer properties, the injection site, and connective tissue characteristics (i.e., tissue, organ, and species dependent) and the dispersal forces exerted onto the bolus (hydrodynamic pressure and local mechanical forces). 11,19,21,22 In general, the intermuscular disposition of the microsuspensions will have implications on the dissolution and absorption kinetics, as the interfascial space possesses characteristics that resemble more the s.c. than the true i.m.…”

Mechanisms of mechanically induced Osteoclastogenesis : in a novel in vitro model for bone implant loosening

“…That influences the pharmacokinetics of systemically of locally delivered drugs. Increased cellular uptake of therapeutics on skeletal muscle cells or nasal epithelial cells has been reported, when the strain was applied [220,221]. This situation could also apply to bone cells, highlighting the importance of drug screening during applied mechanical loading.…”