Pharmacokinetics of methotrexate in rabbit skin and plasma after iv-bolus and iontophoretic administrations.

The pharmacokinetics of methotrexate (MTX) in rabbit's skin and plasma after iv-bolus and iontophoretic delivery at different current densities was studied. Linear microdialysis probes were introduced into the upper dorsal shaved skin of tranquilized rabbits. Commercially available patches were used to deliver MTX for 1 h at different current densities (100, 200, and 300 microA/cm2) on different occasions. Iv-boluses (10 mg/kg) of MTX were also administered. Retrodialysis was performed at the end of the experiments to estimate probe recovery. Plasma and microdialysis samples were analyzed using a validated HPLC assay. Following iv-bolus, MTX showed a bi-exponential decay both in plasma and in skin. Cmax in skin occurred with a delay of 22 min compared with plasma. No quantifiable concentration of MTX was detected in the skin on passive drug delivery. Systemic exposure to MTX (AUC) and Cmax increased linearly with current density. Nevertheless, exposure to MTX in the skin did not increase linearly with current density, whereas Cmax did. In conclusion, iontophoresis remarkably improved the dermal delivery of MTX over passive diffusion. However, total exposure did not increase with current density in the skin, suggesting that for local applications lower current densities may achieve the same effects with minimal systemic exposure.