title: Pharmacokinetics and pharmacodynamics of alfentanil in P-glycoprotein-competent and P-glycoprotein-deficient mice: P-glycoprotein efflux alters alfentanil brain disposition and antinociception.
abstract: Previous studies have indicated that P-glycoprotein (P-gp) attenuates the central nervous system penetration and central activity of some opioids. The impact of P-gp-mediated efflux on the disposition and efficacy of the synthetic opioid alfentanil currently is unknown. In this study, P-gp-competent [mdr1a(+/+)] and P-gp-deficient [mdr1a(-/-)] mice were used to investigate the impact of P-gp-mediated efflux on the systemic pharmacokinetics, brain disposition, and central activity of alfentanil. Equipotent doses of alfentanil were administered to mdr1a(+/+) and mdr1a(-/-) mice (0.2 and 0.067 mg/kg, respectively), and the time course of brain and serum concentrations as well as antinociception were determined. A pharmacokinetic-pharmacodynamic (PK-PD) model was fit to the data and used to assess the impact of P-gp on parameters associated with alfentanil disposition and action. The mdr1a(+/+) mice were less sensitive to alfentanil than mdr1a(-/-) mice, requiring a 3-fold higher dose to produce similar antinociception. PK-PD modeling revealed no differences in alfentanil systemic pharmacokinetics between P-gp expressers and nonexpressers. However, the steady-state brain-to-serum concentration ratio (K(p,brain,ss)) was approximately 3-fold lower in mdr1a(+/+) mice compared with mdr1a(-/-) mice (0.19 +/- 0.01 versus 0.54 +/- 0.04, respectively). Consistent with the approximately 3-fold lower K(p,brain,ss), the antinociception versus serum concentration relationship in mdr1a(+/+) mice was shifted approximately 3-fold rightward compared with mdr1a(-/-) mice. However, there was no difference in the antinociception versus brain concentration relationship, or in the brain tissue EC(50) (11 +/- 1.8 versus 9.2 +/- 1.7 ng/g), between mdr1a(+/+) and mdr1a(-/-) mice. These results indicate that alfentanil is an in vivo P-gp substrate and are consistent with the hypothesis that P-gp-mediated efflux attenuates antinociception by reducing alfentanil K(p,brain,ss).
authors.affiliation: School of Pharmacy Kerr Hall, C.B.#7360, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
authors.forename: J Cory
authors.initials: JC
authors.lastname: Kalvass
authors.forename: Emily R
authors.initials: ER
authors.lastname: Olson
authors.forename: Gary M
authors.initials: GM
authors.lastname: Pollack
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015760:Alfentanil / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010147:Pain Measurement / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D015760:Alfentanil