title: The influence of P-glycoprotein on cerebral and hepatic concentrations of nortriptyline and its metabolites.
abstract: The impact of P-glycoprotein (P-gp) on the distribution of nortriptyline (NT) and its metabolites between brain, liver and serum was studied experimentally. The interaction of NT with P-gp in vitro was confirmed by measurement of P-gp stimulated ATPase activity (Km = 257.6 microM, Vmax = 51.0 nmol phosphate released/mg protein-min). Administration of NT (5 mg/kg, s.c.) to mdrla knockout mice resulted in enhanced brain-serum (1.6-fold, p = 0.012) and liver-serum (1.4-fold, p = 0.019) ratios, as compared to the wild-type mice. For a series of NT doses (2.5, 5, 10, 25, 30 mg/kg, i.p.) inhibition of P-gp with cyclosporine A (CsA, 200 mg/kg, i.p.) in rats led to NT brain- and liver-serum ratios that were on average 1.3- (p = 0.005) and 2.1- (p = 0.001) fold higher than those of the controls, respectively. Verapamil (50 mg/kg) (NT, 5 mg/kg) increased the ratios by a factor of 1.6 (p <0.001) and 10.3 (p <0.001) for brain and liver, respectively. Finally, co-administration of methadone (1 mg/kg) did not alter the brain-serum ratio of NT, but in the liver a slight increase (1.5-fold, p = 0.035) was observed. In conclusion, verapamil yielded complete inhibition of P-gp at the blood-brain barrier and CsA had an effect corresponding to about 50% inhibition. The results show that P-gp influences the penetration of NT into the brain, and that drug-drug interactions may take place.
authors.affiliation: Centre for Basic Psychiatric Research, Psychiatric Hospital, Aarhus, Denmark.
authors.forename: Thomas Broeng
authors.initials: TB
authors.lastname: Ejsing
authors.forename: Jørgen
authors.initials: J
authors.lastname: Hasselstrøm
authors.forename: Kristian
authors.initials: K
authors.lastname: Linnet
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000032:analysis / Q000097:blood / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008691:Methadone / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009661:Nortriptyline / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D000929:Antidepressive Agents, Tricyclic; D004791:Enzyme Inhibitors; D016572:Cyclosporine; D009661:Nortriptyline; D014700:Verapamil; D000251:Adenosine Triphosphatases; D008691:Methadone