Lack of Evidence for Involvement of P-Glycoprotein in Brain Uptake of the Centrally Acting Analgesic, Tramadol in the Rat

Abstract

-Purpose. Tramadol Hydrochloride is a widely-used centrally acting analgesic drug, which has some features of being a P-gp substrate. The present study evaluates the functional involvement of Pgp in CNS distribution of tramadol. Methods. The possibe involvement of P-glycoprotein in brain distribution of tramadol was evaluated using a pharmacokinetic approach in two groups of Pgp-inhibited and control rats. Six male Sprague-Dawley rats were used in each group to collect plasma and brain at 1, 5, 10, and 30 min following two tramadol doses of 1 and 10 mg/kg. Results. The brain uptake clearances of tramadol in Pgp-inhibited and control rats were 2.47±0.56 and 2.34±0.56 ml min , respectively, for 10 mg/kg dose. The brain-to-plasma concentration ratio (Kp,app) of more than 1 in all the time points following both the high and low dose cases (sometimes more than 3) indicated the brain accumulation of the drug. Linear correlation was found between tramadol dose and both corresponding plasma and brain concentrations, but the presence of a dose-dependency was not confirmed by the data obtained for brain-to-plasma concentration ratio. Conclusion. Considering the results of the previous studies and the present research, it seems that the brain accumulation of tramadol is not affected by P-gp inhibition which implies that there may be some other transport mechanisms involved in BBB transport of tramadol.

Pharmacokinetics and physiological effects of repeated oral administrations of tramadol in horses

“…Tramadol accumulation could also have resulted from changes in gastrointestinal absorption due to increase in solubility/permeability and/or active efflux transporter inhibition. Both of these are questionable as tramadol is considered to have high intestinal solubility and permeability (class I of the Biopharmaceutics Classification System) (Lassoued et al, 2011) and the role of P-glycoproteins in the transport of tramadol across cell mem-branes remains unresolved (Slanar et al, 2007;Sheikholeslami et al, 2012). The transient analgesia observed in horses with pain due to chronic laminitis (Guedes et al, 2012) was likely due to reasons other than decreased or inconsistent bioavailability (Giorgi et al, 2007;Shilo et al, 2008;Stewart et al, 2011) as a context-sensitive cumulative effect was detected in this study.…”

“…Tramadol accumulation could also have resulted from changes in gastrointestinal absorption due to increase in solubility/permeability and/or active efflux transporter inhibition. Both of these are questionable as tramadol is considered to have high intestinal solubility and permeability (class I of the Biopharmaceutics Classification System) (Lassoued et al ., ) and the role of P‐glycoproteins in the transport of tramadol across cell membranes remains unresolved (Slanar et al ., ; Sheikholeslami et al ., ).…”

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

“…In situ rat brain perfusion studies by Cisternino et al, showed that tramadol likely shared the same hypothetical proton-coupled antiporter as nicotine and diphenhydramine at the BBB (20). Another rat study found that Pgp inhibition through verapamil pre-treatment had no effect on the brain concentration of tramadol, suggesting it is not a likely P-gp substrate (172).…”

“…In addition, neither tramadol nor its active metabolite Odesmethyltramadol appear to be P-gp substrates, potentially avoiding transporter-mediated interactions with a number of anti-cancer molecules (172,175) …”

Forensic Toxicological Aspects of Tramadol : Focus on Enantioselective Drug Disposition and Pharmacogenetics

“…However, in humans, no loss-of-function mutations have been described [82]. It has not been established if tramadol is a substrate of P-gp, an in vitro study and one in vivo study in rat have suggested that it is not [87,88]. However, venlafaxine, being structurally very similar to tramadol [89], is a P-gp substrate in mice [90].…”