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 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.

Sex hormones regulate cerebral drug metabolism via brain miRNAs: down‐regulation of brain CYP2D by androgens reduces the analgesic effects of tramadol

“…Propranolol attenuated the increases in tramadol‐induced analgesia by orchiectomy, indicated by lower AUC (0–60 min) (31%, P < 0.001) and AUC (0–180 min) levels (56%, P < 0.001) (Figure ). This is consistent with our previous finding that propranolol attenuated the enhancement of tramadol‐induced analgesia following chronic nicotine treatment due to the decreases in nicotine‐induced M1 production via brain CYP2D (Wang et al ., ).…”

“…Propranolol, given i.c.v., attenuated the increase in the production of M1 from tramadol within the brain induced by orchiectomy, which is consistent with previous findings that propranolol decreases the metabolism of codeine and tramadol in rat brain via the inhibition of brain CYP2D (Zhou et al ., ; Wang et al ., ). The inhibition of brain CYP2D by propranolol attenuated the enhancement of tramadol‐induced analgesia induced by orchiectomy.…”

“…The inhibition of brain CYP2D by propranolol attenuated the enhancement of tramadol‐induced analgesia induced by orchiectomy. A previous study revealed that there was no analgesic effect induced by propranolol administration alone (Wang et al ., ). The data indicate that the changes in the pharmacological profile of tramadol by orchiectomy may be at least partly due to the regulation of brain CYP2D by testosterone.…”

“…For CSF sampling, a microdialysis probe was connected to a microperfusion pump (Syringe pump KDS‐101; Kd Scientific, Holliston, MA, USA) and perfused with ACSF at a flow rate of 2 μL·min −1 . CSF samples were directly injected into the HPLC‐MS/MS system and assayed as previously described (Wang et al ., ). To estimate the true drug concentration in CSF, the retrodialysis method was utilized to obtain the in vivo recovery for probe calibration.…”

Kinetics of dextromethorphan-O-demethylase activity and distribution of CYP2D in four commonly-used subcellular fractions of rat brain

“…While mRNA studies have shown that CYP2D4 is the predominant isoform in the rat brain (Funae et al, 2003;Hiroi et al, 1998), other isoforms of CYP2D, such as 2D1 or 2D5, have also been detected in the rat brain, albeit at much lower concentrations (Miksys et al, 2000;Mizuno et al, 2003;Wyss et al, 1995). Studies with rats and monkeys have shown that the concentration and pharmacological response of analgesics and antipsychotics are better correlated with the variability in CYP2D enzyme activity in the brain, as opposed to the hepatic CYP2D (McMillan & Tyndale, 2015;Wang et al, 2015;Zhou et al, 2013). Additionally, induction of brain CYP2D can be independent of its expression in the liver (Mann et al, 2008;Yue et al, 2008).…”