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Regulation of cerebral CYP2D alters tramadol metabolism in the brain : interactions of tramadol with propranolol and nicotine

Wang, Qiaoli LU orcid ; Han, Xiaotong ; Li, Jian ; Gao, Xinghui ; Wang, Yan ; Liu, Mingzhou ; Dong, Guicheng and Yue, Jiang (2015) In Xenobiotica 45(4). p.44-335
Abstract

1. Cytochrome P450 2D (CYP2D) protein is widely expressed across brain regions in human and rodents. We investigated the interactions between tramadol, a clinically used analgesic, and brain CYP2D regulators, by establishing concentration-time curves of tramadol and O-desmethyltramadol (M1) in rat cerebrospinal fluid (CSF) and plasma, as well as by analyzing the analgesia-time course of tramadol. 2. Propranolol (20 μg, intracerebroventricular injection), CYP2D inhibitor, prolonged the elimination t1/2 of tramadol (40 mg/kg, intraperitoneal injection) in the CSF; meanwhile, lower Cmax and AUC0-∞ values of M1 were observed. Nicotine (1 mg base/kg, subcutaneous injection, seven days), brain CYP2D inducer, induced a shorter Tmax and... (More)

1. Cytochrome P450 2D (CYP2D) protein is widely expressed across brain regions in human and rodents. We investigated the interactions between tramadol, a clinically used analgesic, and brain CYP2D regulators, by establishing concentration-time curves of tramadol and O-desmethyltramadol (M1) in rat cerebrospinal fluid (CSF) and plasma, as well as by analyzing the analgesia-time course of tramadol. 2. Propranolol (20 μg, intracerebroventricular injection), CYP2D inhibitor, prolonged the elimination t1/2 of tramadol (40 mg/kg, intraperitoneal injection) in the CSF; meanwhile, lower Cmax and AUC0-∞ values of M1 were observed. Nicotine (1 mg base/kg, subcutaneous injection, seven days), brain CYP2D inducer, induced a shorter Tmax and elevated Cmax of M1 in CSF. No differences in the peripheral metabolism of tramadol were observed following propranolol and nicotine pretreatment. Nicotine increased areas under the analgesia-time curve (AUC) for 0-45 min and 0-90 min of tramadol, which was attenuated by propranolol administration. The analgesic actions of tramadol positively correlated with cerebral M1 concentration. 3. The results suggest that the regulation of brain CYP2D by xenobiotics may cause drug-drug interactions (DDIs) of tramadol. Brain CYPs may play an important role in DDIs of centrally active substances.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Brain/drug effects, Chromatography, Liquid, Cytochrome P-450 Enzyme System/metabolism, Drug Interactions, Male, Nicotine/blood, Propranolol/blood, Rats, Tandem Mass Spectrometry, Tramadol/analogs & derivatives
in
Xenobiotica
volume
45
issue
4
pages
44 - 335
publisher
Taylor & Francis
external identifiers
  • pmid:25387586
  • scopus:84937137640
ISSN
0049-8254
DOI
10.3109/00498254.2014.981609
language
English
LU publication?
no
id
d2763cc2-1033-433c-b5f5-bfe24c7bcecd
date added to LUP
2025-05-12 16:45:32
date last changed
2025-07-17 04:01:31
@article{d2763cc2-1033-433c-b5f5-bfe24c7bcecd,
  abstract     = {{<p>1. Cytochrome P450 2D (CYP2D) protein is widely expressed across brain regions in human and rodents. We investigated the interactions between tramadol, a clinically used analgesic, and brain CYP2D regulators, by establishing concentration-time curves of tramadol and O-desmethyltramadol (M1) in rat cerebrospinal fluid (CSF) and plasma, as well as by analyzing the analgesia-time course of tramadol. 2. Propranolol (20 μg, intracerebroventricular injection), CYP2D inhibitor, prolonged the elimination t1/2 of tramadol (40 mg/kg, intraperitoneal injection) in the CSF; meanwhile, lower Cmax and AUC0-∞ values of M1 were observed. Nicotine (1 mg base/kg, subcutaneous injection, seven days), brain CYP2D inducer, induced a shorter Tmax and elevated Cmax of M1 in CSF. No differences in the peripheral metabolism of tramadol were observed following propranolol and nicotine pretreatment. Nicotine increased areas under the analgesia-time curve (AUC) for 0-45 min and 0-90 min of tramadol, which was attenuated by propranolol administration. The analgesic actions of tramadol positively correlated with cerebral M1 concentration. 3. The results suggest that the regulation of brain CYP2D by xenobiotics may cause drug-drug interactions (DDIs) of tramadol. Brain CYPs may play an important role in DDIs of centrally active substances.</p>}},
  author       = {{Wang, Qiaoli and Han, Xiaotong and Li, Jian and Gao, Xinghui and Wang, Yan and Liu, Mingzhou and Dong, Guicheng and Yue, Jiang}},
  issn         = {{0049-8254}},
  keywords     = {{Animals; Brain/drug effects; Chromatography, Liquid; Cytochrome P-450 Enzyme System/metabolism; Drug Interactions; Male; Nicotine/blood; Propranolol/blood; Rats; Tandem Mass Spectrometry; Tramadol/analogs & derivatives}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{44--335}},
  publisher    = {{Taylor & Francis}},
  series       = {{Xenobiotica}},
  title        = {{Regulation of cerebral CYP2D alters tramadol metabolism in the brain : interactions of tramadol with propranolol and nicotine}},
  url          = {{http://dx.doi.org/10.3109/00498254.2014.981609}},
  doi          = {{10.3109/00498254.2014.981609}},
  volume       = {{45}},
  year         = {{2015}},
}