Pharmacokinetics and Pharmacodynamics of Alfentanil in P-Glycoprotein-Competent and P-Glycoprotein-Deficient Mice: P-Glycoprotein Efflux Alters Alfentanil Brain Disposition and Antinociception

Abstract

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-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 ϳ3-fold lower in mdr1a(؉/؉) mice compared with mdr1a(؊/؊) mice (0.19 ؎ 0.01 versus 0.54 ؎ 0.04, respectively). Consistent with the ϳ3-fold lower K p,brain,ss , the antinociception versus serum concentration relationship in mdr1a(؉/؉) mice was shifted ϳ3-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 .

P-Glycoprotein Is a Major Determinant of Norbuprenorphine Brain Exposure and Antinociception

“…4) to antinociception versus plasma or brain concentrations, where E max was defined as 100%, and ␥ was constrained to be the same for mdr1a(Ϫ/Ϫ) and mdr1a(ϩ/ϩ) mice as described previously (Kalvass et al, 2007).…”

“…In addition, the 8-fold increase in the brain/plasma norbuprenorphine concentration ratio in the absence of P-gp-mediated efflux is greater than that of other opioids. Brain/plasma concentration ratios of morphine, alfentanil, and methadone increased only 2-, 2.4, and 3.5-fold, respectively, in mdr1(Ϫ/Ϫ) mice compared with mdr1(ϩ/ϩ) mice (Zong and Pollack, 2000;Kalvass et al, 2007;Hassan et al, 2009). Moreover, the more than order of magnitude decrease in plasma EC 50 in the absence of P-gp was much greater for norbuprenorphine than for other opioids, such as alfentanil (Kalvass et al, 2007).…”

“…Brain/plasma concentration ratios of morphine, alfentanil, and methadone increased only 2-, 2.4, and 3.5-fold, respectively, in mdr1(Ϫ/Ϫ) mice compared with mdr1(ϩ/ϩ) mice (Zong and Pollack, 2000;Kalvass et al, 2007;Hassan et al, 2009). Moreover, the more than order of magnitude decrease in plasma EC 50 in the absence of P-gp was much greater for norbuprenorphine than for other opioids, such as alfentanil (Kalvass et al, 2007). Thus the degree to which P-gp impedes brain access and antinociception is greater for norbuprenorphine than these other opioids.…”

“…Several opioids have been reported previously in animals and/or humans to be in vitro or in vivo substrates for P-glycoprotein, including loperamide (Wandel et al, 2002;Skarke et al, 2003), morphine (Xie et al, 1999;Wandel et al, 2002;Dagenais et al, 2004), methadone (Dagenais et al, 2004;Kharasch et al, 2004), fentanyl (Wandel et al, 2002;Dagenais et al, 2004), alfentanil (Wandel et al, 2002;Kalvass et al, 2007), and sufentanil (Wandel et al, 2002). Norbuprenorphine has been identified as a substrate for P-gp-mediated efflux by in vitro screening using transfected Madin-Darby canine kidney (MDCK) cells (Tournier et al, 2010).…”

Pharmacokinetics and Pharmacodynamics of Seven Opioids in P-Glycoprotein-Competent Mice: Assessment of Unbound Brain EC50,uand Correlation of in Vitro, Preclinical, and Clinical Data

“…1 was fitted simultaneously to the serum concentration-and brain concentration-time data using nonlinear least-squares regression (WinNonlin 4.1; Pharsight Corporation, Mountain View, CA). The brain volume (V Br ) was fixed at 13.4 ml/kg, assuming a specific gravity of 1.0 g/ml (Kalvass et al, 2007b). All other pharmacokinetic parameters were obtained from fitting the kinetic model to the data.…”