Delivery advantage to the unilateral kidney by direct drug application to the kidney surface in rats and pharmacokinetic verification based on a physiological model

The objective of this study was to evaluate the drug delivery advantage to the unilateral kidney by direct drug application to the rat kidney surface based on a physiological pharmacokinetic model. Under anesthesia, a cylindrical diffusion cell (i.d. 6 mm, area 0.28 cm(2)) was attached to the right kidney surface in rats. Phenolsulfonphthalein (PSP), an organic anion chosen as a model compound, was added into the diffusion cell. The free PSP concentration in the right (applied) kidney after application to the right kidney surface at a dose of 1 mg was significantly higher than that of the left (non-applied) kidney until 60 min after application. Similarly, the urinary excretion rate of free PSP from the applied kidney was much faster than that from the non-applied kidney, with a 2.6 times larger excreted amount in 240 min. These results imply the possibility that a considerable drug delivery advantage to the unilateral kidney could be obtained after direct absorption from the kidney surface. This tendency was also observed at the other application doses of 0.3 and 1.5 mg. On the other hand, fluorescein isothiocyanate dextran (Mw 4400, FD-4) was equally excreted into the urine from each kidney and the renal concentrations in the applied and non-applied kidneys were almost the same, possibly due to the involvement of passive transport for the absorbed FD-4, i.e. glomerular filtration. The computer simulations of free PSP concentrations in the plasma and each kidney based on a physiological model after kidney surface application were consistent with the respective experimental data. Moreover, the delivery advantage of kidney surface application of PSP was verified by its comparison with other routes such as i.v. and i.a. administrations

Alterations of nocturnal activity in rats following subchronic oral administration of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline

1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) is neurotoxic when administered to the brain and alters motor behaviour following intraperitoneal administration. We have assessed the long-term effects of oral TaClo administration on nocturnal motor behaviour in rats. Two groups of rats received TaClo orally at a dose of either 0.2 or 0.4 mg/kg twice daily for 7 weeks. The control group was given saline. No change in locomotor activity was observed 4–9 days after the end of the 7-week administration of TaClo. In addition, the spontaneous motor activity was altered dose-dependently 9 months after oral TaClo administration, with an increase in the low-dose TaClo group and a decrease in the high-dose group. Oral administration of TaClo in rats may be useful in investigating the hypothesis that in Parkinson’s disease, an unknown pathogenic factor crossing the intestinal mucosa barrier can induce neurodegenerative processes eventually affecting the entire brain