Abstract
The excretion, biotransformation, and pharmacokinetics of a selective N-methyl-d-aspartate receptor antagonist, traxoprodil, were investigated in six healthy male volunteers, phenotyped either as CYP2D6 extensive or poor metabolizers of dextromethorphan. Each subject received an i.v. infusion of a single 50-mg (100 μCi) dose of [14C]traxoprodil. Approximately 89% of the administered dose was recovered in poor metabolizers (PMs) and 61% in extensive metabolizers (EMs), with the majority of the dose being excreted in the urine (86% in PMs and 52% in EMs). The elimination of traxoprodil was more rapid in EMs than in PMs with terminal elimination half-lives of 2.8 and 26.9 h, respectively, for EMs and PMs. Area under the plasma concentration-time curve from time 0 to T (AUC(0-Tlast)) values for unchanged traxoprodil were 1.2 and 32.7% of the corresponding AUC values for total radioactivity in EMs and PMs, respectively. Traxoprodil was metabolized in both EMs and PMs, with ∼7 and 50% of the administered radioactivity excreted as unchanged drug in the excreta of EMs and PMs, respectively. Hydroxylation at the 3-position of the hydroxyphenyl ring and methylation of the resulting catechol followed by conjugation were identified as the main metabolic pathways in EMs. In contrast, direct conjugation of traxoprodil with glucuronic or sulfuric acid was the major pathway in PMs. In vitro studies using CYP2D6-selective inhibitor and recombinant enzyme also support that the metabolism of traxoprodil is mainly mediated by CYP2D6. Taken together, these studies suggest that traxoprodil is eliminated mainly by Phase I oxidative metabolism mediated by CYP2D6 isozyme in EMs and by Phase II conjugation and renal clearance of parent in PMs.
Footnotes
- Abbreviations used are::
- Traxoprodil
- CP-101,606, [(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol mesylate]
- NMDA
- N-methyl-d-aspartate
- EM
- extensive metabolizer
- PM
- poor metabolizer
- LC/MS/MS
- liquid chromatography-tandem mass spectrometry
- P450
- cytochrome P450
- HPLC
- high performance liquid chromatography
- LSC
- liquid scintillation counting
- Kel
- the terminal phase rate constant
- T1/2
- terminal phase half-life
- AUC0-T
- area under the plasma concentration-time curve from time 0 to T
- AUMC0-T
- area under the moment curve from time 0 to T
- CLp
- systemic plasma clearance
- MRT
- mean residence time
- VDss
- steady-state volume of distribution
- β-RAM
- radioactive monitor
- CAD
- collisionally activated dissociation
- amu
- atomic mass unit(s)
- MS
- mass spectrometry
- 3-hydroxy-traxoprodil
- 4-[1-hydroxy-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-benzene-1,2-diol
- 3-methoxy-traxoprodil
- 1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol
- 4′-hydroxy-traxoprodil
- 1-[2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl]-4-(4-hydroxy-phenyl)-piperidin-4-ol
- 2-OMe-E2
- 2-methoxy-17β-estradiol
- 2-OH-E2-3ME
- 2-hydroxy-17β-estradiol-3-methyl ether
- Received May 21, 2002.
- Accepted September 28, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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