title: Stereoselective efflux of (E)-10-hydroxynortriptyline enantiomers from the cerebrospinal fluid of depressed patients.
abstract: In 5 patients treated with nortriptyline or amitriptyline for at least 9 months, the cerebrospinal fluid (CSF)/plasma ratio for 10-hydroxynortriptyline (10-OH-NT) ranged from 0.085 to 0.172, which is similar to the ratio previously measured in patients treated for 3 weeks. In 4 other patients treated with racemic (E)-10-OH-NT, the mean concentration ratio between (-)- and (+)-(E)-10-OH-NT was 3.56 in plasma, 2.39 in plasma ultrafiltrate and 1.42 in CSF (one-way ANOVA; P less than 0.001). The mean free fraction in plasma determined by ultrafiltration for (-)-(E)-10-OH-NT was 28.9 +/- S.D.1.1% and for the (+)-enantiomer 43.7 +/- 0.8% (P less than 0.001) confirming the difference in protein binding shown previously in healthy subjects. There was a correlation between the concentration of 10-OH-NT (sum of enantiomers) in CSF and plasma ultrafiltrate (r = 0.96; n = 7; P less than 0.001). The concentration in CSF was, however, only about 50% of that in the plasma ultrafiltrate and this seems to be due to a stereoselective transport of (E)-10-OH-NT out from the CSF. The secretion from the CSF is more pronounced for the (-)-compared to the (+)-enantiomer, which is consistent with the stereoselectivity of the renal secretion of these compounds.
authors.affiliation: Department of Clinical Pharmacology, Karolinska Institute, Huddinge Hospital, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Bertilsson
authors.forename: K
authors.initials: K
authors.lastname: Otani
authors.forename: M L
authors.initials: ML
authors.lastname: Dahl
authors.forename: C
authors.initials: C
authors.lastname: Nordin
authors.forename: A
authors.initials: A
authors.lastname: Aberg-Wistedt
mesh_terms: D000328:Adult; D000639:Amitriptyline / Q000627:therapeutic use; D001693:Biological Transport, Active; D003866:Depressive Disorder / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009661:Nortriptyline / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D011485:Protein Binding; D013237:Stereoisomerism; D014462:Ultrafiltration
chemical_list: C013567:10-hydroxynortriptyline; D000639:Amitriptyline; D009661:Nortriptyline