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

Cutler, Leanne; Howes, Colin; Deeks, Nigel; Buck, Tania; Jeffrey, Phil

doi:10.1002/jps.20658

Cited by 42 publications

(42 citation statements)

References 49 publications

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“…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).…”

Section: Discussionsupporting

confidence: 92%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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ABSTRACT:The magnitude of P-glycoprotein [(P-gp)/multidrug resistance protein 1 (MDR1)]-mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats was estimated by in vitro-in vivo correlation (IVIVC). In in vitro studies, rat Mdr1a-expressing LLC-PK1 cells were examined for the evaluation of P-gp inhibitory activity using digoxin as a P-gp probe substrate. The in vitro K i value was calculated using a modified corrected flux ratio that reflects the P-gp function. In in vivo studies, digoxin with or without P-gp inhibitors was administered to rats by constant intravenous infusion to evaluate the effect of P-gp inhibition on digoxin transport to the brain under steady-state conditions. In the presence of elacridar, the brain-to-plasma concentration ratio (K p,brain ) of digoxin was approximately 14 times the control value. However, no significant change in the K p,brain was observed

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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 […”

mentioning

confidence: 99%

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

Syvänen¹,

Lindhe²,

Palner³

et al. 2008

Drug Metab Dispos

319

271

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ABSTRACT:Species differences occur in the brain concentrations of drugs, but the reasons for these differences are not yet apparent. This study was designed to compare brain uptake of three radiolabeled P-glycoprotein (P-gp) substrates across species using positron emission tomography. Brain concentrations and brain-to-plasma ratios were compared; and minipigs than in rats and guinea pigs. For example, the brainto-plasma ratio of [ 11 C]GR205171 was almost 9-fold higher in humans compared with rats. The species differences were still present after P-gp inhibition, although the increase in brain concentrations after P-gp inhibition was somewhat greater in rats than in the other species. Differences in plasma protein binding and metabolism did not explain the species-related differences. The findings are important for interpretation of brain drug delivery when extrapolating preclinical data to humans. Compounds found to be P-gp substrates in rodents are likely to also be substrates in higher species, but sufficient blood-brain barrier permeability may be retained in humans to allow the compound to act at intracerebral targets.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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

Cited by 42 publications

References 49 publications

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

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

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

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

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