Comparative pharmacokinetics and tendon tissue targeting of topical metformin lotion with protection against experimental tendinopathy

Effective delivery of therapeutics to tendon tissues remains challenging because conventional systemic administration often fails to achieve sufficient local drug concentrations while increasing off-target exposure. To address this limitation, we developed a topical metformin lotion (Met-TL) for transdermal delivery and compared its pharmacokinetics, tendon tissue targeting, and biologic effects with oral, intraperitoneal (IP), and local injection (LI) administration routes in mice. Metformin concentrations in serum and Achilles tendon tissues were quantified using high-performance liquid chromatography (HPLC), while tendon structure and cellular responses were evaluated histologically. Pharmacokinetic analysis demonstrated that Met-TL achieved measurable systemic absorption with a temporal profile comparable to Met-IP administration, with both routes reaching peak serum concentrations at approximately 2 h following treatment. Although systemic exposure following Met-TL remained lower than Met-IP administration, the area under the concentration-time curve for Met-TL exceeded that of oral administration and local injection. Importantly, Met-TL produced significantly greater metformin accumulation within Achilles tendon tissue than oral and IP administration, indicating effective transdermal penetration and enhanced tendon tissue targeting. No overt systemic or local adverse effects were observed, and tendon stem cell morphology and proliferation remained unaffected following treatment. In an intensive treadmill running-induced tendinopathy model, Met-TL improved preservation of tendon structure, collagen organization, and cellular morphology compared with Met-IP administration. Collectively, these findings demonstrate that topical Met-TL enhances tendon tissue targeting while maintaining favorable pharmacokinetic and biologic properties, supporting its potential as a non-invasive therapeutic strategy for tendinopathy.