Stereoselective disposition of racemic E-10-hydroxynortriptyline in human beings.
The disposition and elimination kinetics of the enantiomers of E-10-hydroxynortriptyline (E-10-OH-NT) were studied in six rapid and four slow hydroxylators of debrisoquin after a single oral dose of 75 mg racemic E-10-OH-NT hydrogen maleate. The plasma levels and the AUC of unconjugated (-)E-10-OH-NT were two to five times higher than those of (+)E-10-OH-NT. The plasma half-lives of both enantiomers were 8 to 9 hours. A significantly higher proportion of the given dose of (+)E-10-OH-NT (64.4% +/- 12.1%) than of (-)E-10-OH-NT (35.3% +/- 9.7%) was recovered in urine as glucuronide conjugate, but more (-)E-10-OH-NT was recovered unchanged in urine. The total oral plasma clearance and the metabolic clearance by glucuronidation were significantly (p less than 0.0001) higher for (+)E-10-OH-NT than for (-)E-10-OH-NT. The findings indicate that first-pass glucuronidation of E-10-OH-NT is enantioselective in human beings in vivo, with preference for (+)E-10-OH-NT. The renal clearance of unbound (-)E-10-OH-NT (0.57 +/- 0.16 L.kg-1.hr-1), on the other hand, exceeded that of (+)E-10-OH-NT (0.44 +/- 0.14 L.kg-1.hr-1) (p less than 0.005), which suggests enantioselective tubular secretion. The debrisoquin hydroxylation status was not associated with any of the investigated kinetic processes that relate to E-10-OH-NT.
Dahl-Puustinen
M L
ML
Department of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Sweden.
Perry
T L
TL
Dumont
E
E
von Bahr
C
C
Nordin
C
C
Bertilsson
L
L
D000284:Administration, Oral; D000328:Adult; D005965:Glucuronates / Q000097:blood / Q000652:urine; D006207:Half-Life; D006801:Humans; D008297:Male; D009661:Nortriptyline / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D013237:Stereoisomerism
D005965:Glucuronates; C013567:10-hydroxynortriptyline; D009661:Nortriptyline