![[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}
|
|
|
|
|
||
Anesthesiology Service (E.D.K.), Veterans Affairs Puget Sound
Health Care System; and the Departments of
Anesthesiology (R.B.L.,
E.D.K.),
Medicinal Chemistry (E.D.K.) and
Pharmaceutics (M.F.P.,
K.E.T.), University of Washington
The synthetic opioid fentanyl undergoes extensive metabolism in
humans. Systemic elimination occurs primarily by hepatic metabolism. When administered as a lozenge for oral transmucosal absorption, swallowed fentanyl is subject to first pass metabolism in the liver and
possibly small intestine. Little is known, however, about the identity
and formation of human fentanyl metabolites. This investigation
identified routes of human liver microsomal fentanyl metabolism and
their relative importance, tested the hypothesis that fentanyl is
metabolized by human duodenal microsomes, and identified the
predominantly responsible cytochrome P450 isoforms. A GC/MS assay using
deuterated internal standards was developed for fentanyl metabolites.
Piperidine N-dealkylation to norfentanyl was the
predominant pathway of liver microsomal metabolism. Amide hydrolysis to
despropionylfentanyl and alkyl hydroxylation to hydroxyfentanyl were
comparatively minor pathways. Hydroxynorfentanyl was identified as a
minor, secondary metabolite arising from N-dealkylation of
hydroxyfentanyl. Liver microsomal norfentanyl formation was significantly inhibited by the mechanism-based P450 3A4 inhibitor troleandomycin and the P450 3A4 substrate and competitive inhibitor midazolam, and was significantly correlated with P450 3A4 protein content and catalytic activity. Of six expressed human P450 isoforms (P450s 1A2, 2B6, 2C9, 2D6, 2E1, and 3A4), only P450 3A4 exhibited significant fentanyl dealkylation to norfentanyl. These results indicate the predominant role of P450 3A4 in the primary route of
hepatic fentanyl metabolism. Human duodenal microsomes also catalyzed
fentanyl metabolism to norfentanyl; the average rate was approximately
half that of hepatic metabolism. Rates of duodenal norfentanyl
formation were diminished by troleandomycin and midazolam, and were
significantly correlated with P450 3A4 activity, suggesting a prominent
role for P450 3A4. These results demonstrate that human intestinal as
well as liver microsomes catalyze fentanyl metabolism, and
N-dealkylation by P450 3A4 is the predominant route in both
organs. The fraction of fentanyl lozenge that is swallowed likely
undergoes significant intestinal, as well as hepatic, first-pass
metabolism. Intestinal and hepatic first-pass metabolism, as well as
systemic metabolism, may be subject to individual variability in P450
3A4 expression and to drug interactions involving P450 3A4.
This article has been cited by other articles:
|
|
 |
|
  P.-C. T. Pham, E. Toscano, P.-M. T. Pham, P.-A. T. Pham, S. V. Pham, and P.-T. T. Pham Pain management in patients with chronic kidney disease NDT Plus, April 1, 2009; 2(2): 111 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Douglas, F. Murtagh, E. Chambers, M Howse, and J Ellershaw Symptom management for the adult patient dying with advanced chronic kidney disease: A review of the literature and development of evidence-based guidelines by a United Kingdom Expert Consensus Group Palliative Medicine, March 1, 2009; 23(2): 103 - 110. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Darwish, M. Kirby, P. Robertson Jr, W. Tracewell, and J. G. Jiang Absolute and Relative Bioavailability of Fentanyl Buccal Tablet and Oral Transmucosal Fentanyl Citrate J. Clin. Pharmacol., March 1, 2007; 47(3): 343 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mayes and M. Ferrone Fentanyl HCl Patient-Controlled Iontophoretic Transdermal System for the Management of Acute Postoperative Pain Ann. Pharmacother., December 1, 2006; 40(12): 2178 - 2186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-F. Marier, M. Lor, D. Potvin, M. DiMarco, G. Morelli, and E. A. Saedder Pharmacokinetics, Tolerability, and Performance of a Novel Matrix Transdermal Delivery System of Fentanyl Relative to the Commercially Available Reservoir Formulation in Healthy Subjects. J. Clin. Pharmacol., June 1, 2006; 46(6): 642 - 653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. G. Fritz, M. Holzmayr, B. Walter, K.-U. Moeritz, A. Lupp, and R. Bauer The Effect of Mild Hypothermia on Plasma Fentanyl Concentration and Biotransformation in Juvenile Pigs Anesth. Analg., April 1, 2005; 100(4): 996 - 1002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. D. Kharasch, C. Hoffer, T. G. Altuntas, and D. Whittington Quinidine as a Probe for the Role of P-Glycoprotein in the Intestinal Absorption and Clinical Effects of Fentanyl J. Clin. Pharmacol., March 1, 2004; 44(3): 224 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. D. Quang-Cantagrel, M. S. Wallace, and S. K. Magnuson Opioid Substitution to Improve the Effectiveness of Chronic Noncancer Pain Control: A Chart Review Anesth. Analg., April 1, 2000; 90(4): 933 - 937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Matsui, M. Mishima, Y. Nagai, T. Yuzuriha, and T. Yoshimura Absorption, Distribution, Metabolism, and Excretion of Donepezil (Aricept) after a Single Oral Administration to Rat Drug Metab. Dispos., December 1, 1999; 27(12): 1406 - 1414. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. K. Henthorn, Y. Liu, M. Mahapatro, and K.-y. Ng Active Transport of Fentanyl by the Blood-Brain Barrier J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 1084 - 1089. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
