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Pharmacokinetics of amitriptyline in rabbit skin and plasma following iontophoretic administrations

Background: Amitriptyline (AMT) is a tricyclic antidepressant with demonstrated local analgesic effects in human skin. Aim: We investigated the feasibility and mechanisms of iontophoretic delivery of AMT to rabbit dermis and plasma. Method: Two microdialysis probes were inserted into the upper dorsal shaved skin of tranquilized rabbits. After 1 hour, an iontophoresis cartridge was placed on top of one probe. The cartridge consisted of a stainless steel electrode covered with a pad that was filled with a 4.3 % AMT glycerin/water (50:50). Iontophoresis was performed at 100, 200, or 300 μA/cm2 constant-current density for 60 minutes. Dialysate samples were collected every 8 minutes for 3 hours and analyzed for AMT via a validated high-performance liquid chromatographic assay. Retrodialysis was performed at the other site. Blood samples were collected serially for 4 hours. Results: In vivo retrodialysis recovery was 89 ± 2%. AMT skin exposure increased non-proportionally with current density: AUCs were 19 ± 7, 119 ± 56, and 615 ± 302 mg/L/min for the 100, 200, and 300 μA/cm2, respectively, and Cmax were 107 ± 15, 1070 ± 537, and 5870 ± 1289 μg/L. In vivo plasma concentrations were always below LLOQ (0.1 μg/mL). Conclusion: AMT can be administered by iontophoresis and produces significant skin concentrations and negligible plasma levels.