Influence of P-glycoprotein inhibition on the distribution of the tricyclic antidepressant nortriptyline over the blood–brain barrier

✍ Scribed by Thomas B. Ejsing; Kristian Linnet

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 77 KB
• Volume: 20
• Category: Article
• ISSN: 0885-6222
• DOI: 10.1002/hup.667

✦ Synopsis

The distribution of the antidepressant drug nortriptyline (NT) and its main metabolite E-10-hydroxy-nortriptyline (E-10-OH-NT) across the blood-brain barrier was considered in relation to inhibition of the multidrug transporter P-glycoprotein (P-gp). Rats received NT in doses of 25 mg/kg orally, 10 mg/kg i.p. or 25 mg/kg i.p. Half the rats were treated with the Pglycoprotein inhibitor cyclosporine A (CsA) (200 mg/kg) 2 h prior to NT administration, and the other half served as a control group. NT and the metabolite were extracted from brain and serum by liquid-liquid extraction and analysed by HPLC with UV-detection. The brain to serum ratio of NT was increased in the CsA treated groups (22.3-26.8) compared with the control groups (16.5-22.7), the difference being statistically significant in two of the three experiments ( p < 0.05). Increased brain-serum ratios were also found for E-10-OH-NT, but the differences were not statistically significant. These results suggest that inhibition of P-gp by CsA increases the accumulation of NT in the brain. Administration of the antipsychotic drug risperidone (0.5 mg/kg s.c.), which is a P-gp substrate, instead of CsA did not exert any measurable influence on the blood-brain ratio of NT concentrations.

In conclusion, the results show that drug-drug interaction at P-gp may influence the intracerebral NT concentration, but apparently, a major inhibition of P-gp is necessary to attain a measurable effect.