Pharmacokinetics and pharmacodynamics of alfentanil in P-glycoprotein- competent and P-glycoprotein-deficient mice: P-glycoprotein efflux alters alfentanil brain disposition and antinociception

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-gpdeficient [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 ∼3-fold lower in mdr1a(+/+) mice compared with mdr1a(-/-) mice (0.19 ± 0.01 versus 0.54 ± 0.04, respectively). Consistent with the ∼3-fold lower K_p,brain,ss, the antinociception versus serum concentration relationship in mdr1a(+/+) mice was shifted ∼3-fold rightward compared with mdr1a(-/-) mice. However, there was no difference in the antinociception versus brain concentration relationship, or in the brain tissue EC₅₀ (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.