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

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 t_1/2 of tramadol (40 mg/kg, intraperitoneal injection) in the CSF; meanwhile, lower C_max and AUC_0–∞ values of M1 were observed. Nicotine (1 mg base/kg, subcutaneous injection, seven days), brain CYP2D inducer, induced a shorter T_max and elevated C_max 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.

• Brain
• cytochrome P450 2D
• nicotine
• propranolol
• tramadol

Declaration of interest

This work was supported by the Program for New Century Excellent Talents in University (NCET-11-0399) and the National Natural Science Foundation of China (No. 81173122, 30973582 and 30960334). The authors report no conflicts of interest.