title: Effect of P-glycoprotein inhibition on methadone analgesia and brain distribution in the rat.
abstract: 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Barrio Sarriena s/n 48940, Leioa, Vizcaya, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Ortega
authors.forename: Itziar
authors.initials: I
authors.lastname: Soengas
authors.forename: Elena
authors.initials: E
authors.lastname: Suarez
authors.forename: John C
authors.initials: JC
authors.lastname: Lukas
authors.forename: Rosario
authors.initials: R
authors.lastname: Calvo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000284:Administration, Oral; D000698:Analgesia / Q000379:methods*; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003524:Cyclosporins / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006358:Hot Temperature / Q000009:adverse effects; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008691:Methadone / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D003524:Cyclosporins; C070272:valspodar; D008691:Methadone