Effect of P-glycoprotein inhibition on methadone analgesia and brain distribution in the rat.

Methadone is an opiate drug that has been identified as an in-vitro substrate of the efflux pump P-glycoprotein (P-gp), active in the intestinal epithelium and in the blood-brain barrier (BBB), among other sites. The objective of this study was to test in vivo, in the rat model, the role of P-gp modulation on the analgesic effect and brain uptake of methadone, as well as identify the most relevant site via dual oral and intravenous (i.v.) experiments. The P-gp specific inhibitor (valspodar or PSC833) was preadministered (10 mg kg(-1) i.v.) to test groups. Analgesia was measured using the tailflick test. The ED50 for oral methadone (2, 3, 6 and 8 mg kg(-1)) decreased three-fold in valspodar groups compared with controls (2.23 +/- 0.002 mg kg(-1) and 6.07 +/- 0.07 mg kg(-1); P < 0.0001). The overall analgesic effect (% antinociception) was elevated 3.1 times in pretreated compared with control rats (90.65% +/- 0.22 vs 29.23% +/- 14.0; P < 0.01) after 6 mg kg(-1) oral methadone and 2.8 times after i.v. (0.35 mg kg(-1)) administration (91.75% +/- 4.27 vs 32.45% +/- 9.0; P < 0.01). The brain:plasma distribution ratio was higher in pretreated animals and AUCbrain (overall brain concentration) was 6 times higher after oral methadone and 4 times higher after i.v. compared with controls, disproportionally increased relative to plasma, implying an active process at the BBB. P-gp, and hence substrate comedication, plays a critical role in the evolution of the methadone analgesic effect and in its brain uptake, independent of the administration route.