Development of a P-Glycoprotein Knockout Model in Rodents to Define Species Differences in its Functional Effect at the Blood–brain Barrier

Quantitative Investigation of the Impact of P-Glycoprotein Inhibition on Drug Transport across Blood-Brain Barrier in Rats

“…In addition, the apparent EC 50 of elacridar plasma concentration to achieve chemically induced P-gp knockout in rats was 266 ng/ml. This result was also comparable to the previous report (EC 50 , Ϸ320 ng/ml) using elacridar-treated rats (Cutler et al, 2006). The unbound EC 50 was approximately 2.7 ng/ml (4.7 nM), which was in good agreement with the in vitro K i value (Table 2).…”

“…The use of Mdr1a/Mdr1b(Ϫ/Ϫ) mice and chemically induced P-gp knockout animals for investigating the importance of P-gp at the BBB has been reported previously (Schinkel et al, 1994(Schinkel et al, , 1995Cutler et al, 2006). The use of gene knockout mice for the functional evaluation of transporters is a long-established tradition; however, the advantage of chemically induced P-gp knockout animals is that any species relevant to the pharmacological model can be used to examine the effect of P-gp on drug efficacy and dose response.…”

Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport

“…Another in vitro study showed that the IC 50 value of typical P-gp inhibitors differed with species and substrate (Suzuyama et al, 2007). Cutler et al (2006) demonstrated in vivo differences between rats and guinea pigs in the IC 90 value of the P-gp inhibitor GF-120918. They showed that a higher plasma concentration of GF-120918 was needed in guinea pigs than in rats to achieve the same level of P-gp inhibition.…”

“…Besides differences in substrate affinity, differences in P-gp expression could also result in differences in P-gp transport capacity. In vivo evidence for species differences in P-gp function has so far only been reported by one group, who compared rats and guinea pigs and found that higher concentrations of the P-gp inhibitor GF-120918 were needed in guinea pigs than in rats to achieve the same increase in brain concentrations of an undisclosed P-gp substrate (Cutler et al, 2006). In contrast, when Hsiao et al (2006) compared the increase of […”

Evaluation of P-glycoprotein expression in pain relevant tissues: understanding translation of efflux from preclinical species to human

“…These results indicate species differences in P-gp function despite the high degree of homology in the amino acid content across species. In vivo evidence for species differences in P-gp function has been demonstrated by Cutler et al, who found that higher concentrations of the P-gp inhibitor GF-120918 were needed in guinea pigs than in rats to achieve the same increase in brain concentrations of an undisclosed P-gp substrate [9]. Besides differences in substrate affinity, differences in P-gp expression levels could also result in differences in P-gp transport capacity.…”