![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Drug Metabolism (K.K., E.M., T.G., A.M., R.M.G.), Eli
Lilly and Company, Lilly Corporate Center;
Lilly Laboratory for
Clinical Research (E.N., B.O., J.T.C., L.L.); and Departments of
Medicine (J.T.C.) and
Pharmacology (J.T.C., L.L.),
Indiana University
School of Medicine and Lilly Research Centre (D.T.)
Disposition and biotransformation of the new antipsychotic agent
olanzapine (OLZ) were studied in six male healthy volunteers after a
single oral dose of 12.5 mg containing 100 µCi of
[14C]OLZ. Biological fluids were analyzed for total
radioactivity, the parent compound (GC/MS), and metabolites
(electrospray LC/MS and LC/MS/MS). Mean radiocarbon recovery was
~87%, with 30% appearing in the feces and 57% excreted in the
urine. Approximately half of the radiocarbon was excreted within 3 days, whereas >70% of the dose was recovered within 7 days of dosing.
Circulating radioactivity was mostly restricted to the plasma
compartment of blood. Mean peak plasma concentration of OLZ was 11 ng/ml, whereas that of radioactivity was 39 ng eq/ml. Mean plasma
terminal elimination half-lives were 27 and 59 hr, respectively, for
OLZ and total radioactivity. With the help of NMR and MS data, a major
metabolite of OLZ in humans was characterized as a novel tertiary
N-glucuronide in which the glucuronic acid moiety is
attached to the nitrogen at position 10 of the benzodiazepine ring.
Another N-glucuronide was detected in urine and identified
as the quaternary N-linked 4
-N-glucuronide.
Oxidative metabolism on the allylic methyl group resulted in
2-hydroxymethyl and 2-carboxylic acid derivatives of OLZ. The methyl
piperazine moiety was also subject to oxidative attack, giving rise to
the N-oxide and N-desmethyl metabolites. Other
metabolites, including the N-desmethyl-2-carboxy
derivative, resulted from metabolic reactions at both the 4 nitrogen
and 2-methyl groups. The 10-N-glucuronide and OLZ were the
two most abundant urinary components, accounting for ~13% and 7% of
the dose, respectively. In fecal extracts, the only significant
radioactive HPLC peaks were due to 10-N-glucuronide and OLZ
representing, respectively, ~8% and 2% of the administered dose.
Semiquantitative data obtained from plasma samples from subjects given
[14C]OLZ suggest that the main circulating metabolite is
10-N-glucuronide. Thus, OLZ was extensively metabolized in
humans via N-glucuronidation, allylic hydroxylation,
N-oxidation, N-dealkylation and a combination thereof. The 10-N-glucuronidation pathway was the most
important pathway both in terms of contribution to drug-related
circulating species and as an excretory product in feces and urine.
This article has been cited by other articles:
|
|
 |
|
  Y. E. Savoy, M. A. Ashton, M. W. Miller, F. M. Nedza, D. K. Spracklin, M. H. Hawthorn, H. Rollema, F. F. Matos, and E. Hajos-Korcsok Differential Effects of Various Typical and Atypical Antipsychotics on Plasma Glucose and Insulin Levels in the Mouse: Evidence for the Involvement of Sympathetic Regulation Schizophr Bull, August 14, 2008; (2008) sbn104v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Chiu, H.-Y. Lane, M.-C. Huang, H.-C. Liu, M. W. Jann, Y.-Y. Hon, W.-H. Chang, and M.-L. Lu Dose-Dependent Alternations in the Pharmacokinetics of Olanzapine During Coadministration of Fluvoxamine in Patients With Schizophrenia J. Clin. Pharmacol., December 1, 2004; 44(12): 1385 - 1390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-Y. Wang, Z.-J. Zhang,, W.-B. Li, Y.-M. Zhai, Z.-J. Cai, Y.-Z. Weng, R.-H. Zhu, J.-P. Zhao, and H.-H. Zhou The Differential Effects of Steady-State Fluvoxamine on the Pharmacokinetics of Olanzapine and Clozapine in Healthy Volunteers J. Clin. Pharmacol., July 1, 2004; 44(7): 785 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gervasini, S. Vizcaino, A. G. Herraiz, J. Benitez, and J. A. Carrillo Applicability of an Assay for Routine Monitoring of Highly Variable Concentrations of Olanzapine Based on HPLC with Mass Spectrometric Detection Clin. Chem., December 1, 2003; 49(12): 2088 - 2091. [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Gardiner, J. H. Kristensen, E. J. Begg, L. P. Hackett, D. A. Wilson, K. F. Ilett, R. Kohan, and J. Rampono Transfer of Olanzapine Into Breast Milk, Calculation of Infant Drug Dose, and Effect on Breast-Fed Infants Am J Psychiatry, August 1, 2003; 160(8): 1428 - 1431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Breyer-Pfaff and H. Wachsmuth Tertiary N-Glucuronides of Clozapine and Its Metabolite Desmethylclozapine in Patient Urine Drug Metab. Dispos., October 1, 2001; 29(10): 1343 - 1348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Schaber, G. Wiatr, H. Wachsmuth, M. Dachtler, K. Albert, I. Gaertner, and U. Breyer-Pfaff Isolation and Identification of Clozapine Metabolites in Patient Urine Drug Metab. Dispos., June 1, 2001; 29(6): 923 - 931. [Abstract] [Full Text]
|
|
|
|
|
|
U. Mey, H. Wachsmuth, and U. Breyer-Pfaff Conjugation of the Enantiomers of Ketotifen to Four Isomeric Quaternary Ammonium Glucuronides in Humans In Vivo and in Liver Microsomes Drug Metab. Dispos., November 1, 1999; 27(11): 1281 - 1292. [Abstract] [Full Text]
|
|
|
|
|
|
S.-H. L. Chiu and S.-E. W. Huskey Species Differences in N-Glucuronidation Drug Metab. Dispos., September 1, 1998; 26(9): 838 - 847. [Abstract] [Full Text]
|
|
|
|
|
|
K. Kassahun, E. Mattiuz, R. Franklin, and T. Gillespie Olanzapine 10-N-Glucuronide. A Tertiary N-Glucuronide Unique to Humans Drug Metab. Dispos., September 1, 1998; 26(9): 848 - 855. [Abstract] [Full Text]
|
|
|
|
|
|
E. Mattiuz, R. Franklin, T. Gillespie, A. Murphy, J. Bernstein, A. Chiu, T. Hotten, and K. Kassahun Disposition and Metabolism of Olanzapine in Mice, Dogs, and Rhesus Monkeys Drug Metab. Dispos., May 1, 1997; 25(5): 573 - 583. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
