Pharmacokinetics of amitriptyline N-oxide in rats after single and prolonged oral administration.

Amitriptyline N-oxide (AMINO) was given to male Wistar rats orally in single and multiple doses, and the levels of the drug and its main metabolite amitriptyline (AMI) were assayed in blood and brain by HPLC. After the single dose of AMINO (20 mg/kg), the levels of the parent compound and of AMI in the brain were higher than in blood. In the brain Cmax of AMINO and AMI were similar, whereas in the blood Cmax of AMI was considerably lower than that of the parent compound. After chronic treatment with AMINO (10 mg/kg twice daily, at 12 h intervals, for 14 days) the brain level of AMI reached the value of approx. 4 micrograms/g of tissue and remained nearly stable for 12 h after the last dose. Brain Cmax of AMINO was approx. 2 micrograms/g; the drug was eliminated more rapidly than AMI and 24 h after the last dose it was not detectable. The blood level of AMINO exceeded the level of AMI, but the difference was less marked than that observed after a single dose. The brain and blood levels of both drugs were considerably higher than those observed in the acute experiment. When AMI was given to rats chronically (dosage and schedule as above) its blood and brain levels were 2-5 times higher than the corresponding levels of AMI after treatment with AMINO, and its elimination was more rapid. Our results indicate that after oral administration of AMINO to rats AMI is formed in significant amounts, its brain level is high and becomes more stable after chronic treatment.