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Stereoselective disposition of racemic E-10-hydroxynortriptyline in human beings.
- Source :
-
Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 1989 Jun; Vol. 45 (6), pp. 650-6. - Publication Year :
- 1989
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 0009-9236
- Volume :
- 45
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Clinical pharmacology and therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 2731406
- Full Text :
- https://doi.org/10.1038/clpt.1989.86