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.

In vitro P-Glycoprotein-Mediated Transport of (R)-, (S)-, (R,S)-Methadone, LAAM and Their Main Metabolites

“…Our current finding of methadone being a substrate of P-gp is in agreement with previous in vitro studies using the everted gut sac model [19] and human trophoblastlike cell line (Be-Wo) [20] as models, and with in vivo studies on rats and knockout mice [22][23][24] . Contradictory results have been published using Caco-2 cells [21] , but as most methods reached the same conclusion, methadone is most likely to be a P-gp substrate.…”

“…In vivo, studies with P-gp knockout mice or rats treated with a specific P-gp inhibitor have shown that the analgesic effect of methadone was greater and its brain concentrations were markedly higher when P-gp was absent or inhibited [22][23][24] . One study quantified the enantiomers of methadone, suggesting a stereoselectivity in its transport by mouse P-gp, with an observed apparent lower brain access for (S)-methadone [23] .…”

Effects of Prenatal Cocaine Exposure on Human Pregnancy and Postpartum

“…Because co-consumption of methadone with other drugs such as cocaine and heroin is frequent, additional drugs may influence the placental transfer of methadone and other substances by different mechanisms. In case of inhibition of the P-glycoprotein (P-gp) function by other drugs, the placental barrier may disrupt, and P-gp substrates may increasingly transfer to fetal circulation [87,88]. The P-gp which is expressed in the brush-border of the placental syncytiotrophoblast and this syncytial layer is floating in the maternal blood.…”

“…The P-gp which is expressed in the brush-border of the placental syncytiotrophoblast and this syncytial layer is floating in the maternal blood. The P-gp is an efflux transporter meaning the protection of the placenta and the fetus against many drugs [87,88]. In a second perfusion study [89], the effect of the combined cocaine plus methadone on the placental function was investigated.…”

Cyclosporine-inhibitable Cerebral Drug Transport Does Not Influence Clinical Methadone Pharmacodynamics

“…17 In rats, methadone co-administration with the ABC transport inhibitor PSC833 (valspodar) increased methadone brain concentrations and antinociception, and reduced the dose for half-maximal effect (ED 50 ). 18 Together, these studies suggest that methadone is a substrate for P-gp, and brain P-gp-mediated transport influences brain access and pharmacologic effect.…”