Percutaneous Pharmacokinetics and Material Balance Studies with Glutaraldehyde

Abstract

Material balance and pharmacokinetic studies were conducted in Fischer 344 rats and New Zealand White rabbits of both sexes after intravenous or epicutaneous dosing with [14C]glutaraldehyde. Concentrations of glutaraldehyde used were 0.075, 0.75, and 7.5% (w/w), with dose volumes of 0.2 ml for rats and 2.5 ml for rabbits. Rats and rabbits received the lower two concentrations for the intravenous studies and the upper two for the dermal studies; rats also received 0.075% for the dermal material balance studies. The corresponding dosage levels were approximately 0.58, 6.5, and 63 ml/kg for male rats; 0.85, 8.7, and 102 mg/kg for female rats; and 0.62, 6.3, and 60 mg/kg for rabbits of both sexes.In the intravenous material balance study, the recovery of radiochemical ranged from 86 to 101%. In both rats and rabbits the principal route of radiochemical excretion was as 14CO2 at 22-80% of the administered dose. Urinary excretion ranged from 7 to 28%, and that in feces was 0.2 to 5%. Rabbits excreted proportionally more radiochemical in the urine and less in the feces than rats. Highest concentrations of radiochemical were in blood cells, spleen, lung, and kidney of both species at 24-hr postdosing. Shifts in the elimination pathway of the radiochemical suggest a possible saturation of the disposition mechanisms for glutaraldehyde at 0.75% given intravenously. Urinary radiochromatograms suggest that the rabbit is capable of forming one more acidic metabolite than the rat.After epicutaneous administration of [14C]glutaraldehyde to 12-15% of the total body surface area, the largest proportion of radiochemical was recovered in the skin of the dosing area (31-61%). Autoradiography demonstrated the radiolabel to be predominantly associated with the stratum cornea, the outermost regions of hair shafts and follicles, and foci of dermal necrosis. In the dermal material balance studies, rabbits absorbed 33-53% of the administered dose, and rats between 4.1 and 8.7%. Other than the skin of the dosing area, there was no consistent accumulation of radiochemical in any tissue.The pharmacokinetic studies indicated that the mean concentrations of radiochemical in animals receiving epicutaneous [14C]glutaraldehyde were 100-1000 times less than those following the intravenous injection of corresponding concentrations of glutaraldehyde. The mean concentration of plasma radiochemical was higher in rabbits than rats after the epicutaneous application of corresponding concentrations of [14C]glutaraldehyde. The absorption rate constraints were low in both species, ranging from 0.2 to 2.0/hr. Terminal half-life values were longer in rabbits than rats for [14C]glutaraldehyde given by the intravenous route. Also, the terminal half-life values were significantly longer following epicutaneous than intravenous dosing. Areas under the curve of plasma radiochemical versus time indicated that under the conditions of the pharmacokinetic studies rats percutaneously absorbed 0.3-2.1% radiochemical, and rabbits 2.5-15.6%.