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% (Lo), demonstrating biologic significance of Lo and impact of fiber size and distribution on function and pharmacokinetics. Overall penetration decreased but relative enhancement of penetration at Lo 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.