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P-glycoprotein is a Major Determinant of Norbuprenorphine Brain Exposure and Antinociception.

J Pharmacol Exp Ther. 2012 Jun 27;

Authors: Brown SM, Campbell SD, Crafford A, Regina KJ, Holtzman MJ, Kharasch ED


Norbuprenorphine is a major metabolite of buprenorphine and potent agonist of mu, delta and kappa opioid receptors. Compared to buprenorphine, norbuprenorphine causes minimal antinociception but greater respiratory depression. It is unknown whether the limited antinociception is due to low efficacy or to limited brain exposure. Norbuprenorphine is an in vitro substrate of the efflux transporter P-glycoprotein (Mdr1), but the role of P-glycoprotein in norbuprenorphine transport in vivo is unknown. This investigation tested the hypothesis that limited norbuprenorphine antinociception results from P-gp mediated efflux and limited brain access. Human P-glycoprotein-mediated transport in vitro of buprenorphine, norbuprenorphine and their respective glucuronide conjugates was assessed using transfected cells. P-glycoprotein-mediated norbuprenorphine transport and consequences in vivo were assessed using mdr1a(+/+) and mdr1a(-/-) mice. Antinociception was determined by hot water tail-flick assay and respiratory effects by unrestrained whole body plethysmography. Brain and plasma norbuprenorphine and norbuprenorphine-3-glucuronide were quantified by mass spectrometry. In vitro, the net P-glycoprotein-mediated efflux ratio for norbuprenorphine was 9, indicating significant efflux. In contrast, the efflux ratio for buprenorphine and the two glucuronide conjugates was unity, indicating absent transport. The norbuprenorphine brain/plasma concentration ratio was significantly greater in mdr1a(-/-) than mdr1a(+/+) mice. The magnitude and duration of norbuprenorphine antinociception were significantly increased in mdr1a(-/-) compared with mdr1a(+/+) mice, whereas the reduction in respiratory rate was similar. Results show that norbuprenorphine is an in vitro and in vivo substrate of P-glycoprotein. P-glycoprotein-mediated efflux influences the brain access and antinociceptive but not the respiratory effects of norbuprenorphine.

PMID: 22739506 [PubMed - as supplied by publisher]