In Vivo Evaluation of P-glycoprotein Function at the Blood-Brain Barrier in Nonhuman Primates Using [<sup>11</sup>C]Verapamil

Lee, Young‐Joo; Maeda, Jun; Kusuhara, Hiroyuki; Okauchi, Takashi; Inaji, Motoki; Nagai, Yuji; Obayashi, Shigeru; Nakao, Ryuji; Suzuki, Kazutoshi; Sugiyama, Yuichi; Suhara, Tetsuya

doi:10.1124/jpet.105.088328

Cited by 80 publications

(57 citation statements)

References 30 publications

(36 reference statements)

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“…Recently, the P-gp function at the blood-brain barrier was evaluated in monkeys using a specific P-gp inhibitor (PSC833) by a positron emission tomography technique (Lee et al, 2006). However, the magnitude of the increase observed in PSC833-treated monkeys was not as high as that observed in P-gp knockout mice.…”

Section: Resultsmentioning

confidence: 99%

Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies

Kitamura

Koto²,

Matsuura³

et al. 2008

Drug Metab Dispos

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ABSTRACT:P-glycoprotein (P-gp), encoded by the multidrug resistance 1 gene (MDR1/ABCB1), exhibits very broad substrate specificity and plays important roles in drug disposition. The purpose of the present study was to examine the effect of impaired P-gp activity on the plasma pharmacokinetics of P-gp substrates in collies with or without homozygous mutant alleles producing truncated P-gp. Three therapeutic agents, fexofenadine (0.1 mg/kg), quinidine (0.1 mg/kg), and loperamide (0.01 mg/kg), were simultaneously given orally, and their plasma concentration-time profiles were determined. The plasma concentrations of these drugs tended to be higher in dogs with the homozygous mutated allele. The C max was 53.9 ؎ 13.1 and 90.7 ؎ 23.1 ng/ml for fexofenadine, 16.5 ؎ 3.4 and 20.0 ؎ 7.9 ng/ml for quinidine, and 80.8 ؎ 9.0 and 101 ؎ 15 pg/ml for loperamide, and the AUC 0-8 was 263 ؎ 62 and 435 ؎ 95 ng⅐h/ml for fexofenadine, 54.5 ؎ 11.5 and 75.7 ؎ 21.8 ng⅐h/ml for quinidine, and 467 ؎ 85 and 556 ؎ 91 pg⅐h/ml for loperamide in homozygous wild-type and homozygous mutated dogs, respectively. Only the plasma concentration differences of fexofenadine at 4 to 8 h after oral administration were statistically significant. This result suggests that P-gp limits the intestinal absorption of fexofenadine in dogs. Collies with the Mdr1 mutation will be useful for examining the effect of P-gp on the oral availability of drugs.

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Section: Resultsmentioning

confidence: 99%

Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies

Kitamura

Koto²,

Matsuura³

et al. 2008

Drug Metab Dispos

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“…Although our study of [ 11 C]verapamil included only two PET scans in monkeys, one untreated monkey and one monkey receiving CsA, our results are in line with those in other publications. For example, Lee et al (2006) studied uptake of […”

Section: Species Differences In Blood-brain Barrier Transportmentioning

confidence: 99%

“…[ 11 C]Verapamil is the most frequently used PET radioligand for P-gp studies (Hendrikse et al, 1999;Bart et al, 2003;Sasongko et al, 2005;Lee et al, 2006;Syvänen et al, 2006 (Doze et al, 2000;Bart et al, 2005;de Vries et al, 2005;Lazarova et al, 2008;Zoghbi et al, 2008). Some radioligands shown to be P-gp substrates in rodents are nonetheless taken up by the brain in primates, indicating that there may be species differences in P-gp function.…”

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

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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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“…Among numerous 11 C-labeled P-gp substrates, 11 Cverapamil has been well characterized (18)(19)(20). Cyclosporine A and its analog significantly increase clearance of 11 C-verapamil in the brain of monkeys and healthy humans (19,21).…”

mentioning

confidence: 99%

“…Cyclosporine A and its analog significantly increase clearance of 11 C-verapamil in the brain of monkeys and healthy humans (19,21). 11 C-verapamil has been used to investigate variations in P-gp function at the BBB caused by single-nucleotide polymorphisms (22) and by Parkinson disease (23).…”

mentioning

confidence: 99%

Developmental Changes in P-Glycoprotein Function in the Blood–Brain Barrier of Nonhuman Primates: PET Study with R-¹¹C-Verapamil and ¹¹C-Oseltamivir

Takashima

Yokoyama²,

Mizuma³

et al. 2011

J Nucl Med

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P-glycoprotein (P-gp) plays a pivotal role in limiting the penetration of xenobiotic compounds into the brain at the blood-brain barrier (BBB), where its expression increases with maturation in rats. We investigated developmental changes in P-gp function in the BBB of nonhuman primates using PET with R-11 C-verapamil, a PET radiotracer useful for evaluating P-gp function. In addition, developmental changes in the brain penetration of 11 C-oseltamivir, a substrate for P-gp, was investigated as practical examples. Methods: PET studies in infant (age, 9 mo), adolescent (age, 24-27 mo), and adult (age, 5.6-6.6 y) rhesus monkeys (Macaca mulatta) were performed with R-11 C-verapamil and also with 11 C-oseltamivir. Arterial blood samples and PET images were obtained at frequent intervals up to 60 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots using data collected within the first 2.5 min after tracer administration. Results: R-11 C-verapamil rapidly penetrated the brain, whereas the blood concentration of intact R-11 C-verapamil decreased rapidly in all subjects. The maximum brain uptake in infant (0.033% 6 0.007% dose/g of brain) and adolescent (0.020% 6 0.002% dose/ g) monkeys was 4.1-and 2.5-fold greater, respectively, than uptake in adults (0.0082% 6 0.0007% dose/g). The clearance of brain R-11 C-verapamil uptake in adult monkeys was 0.056 6 0.010 mL/min/g, significantly lower than that in infants (0.11 6 0.04 mL/min/g) and adolescents (0.075 6 0.023 mL/min/g). 11 C-oseltamivir showed little brain penetration in adult monkeys, with a clearance of R-11 C-verapamil uptake of 0.0072 and 0.0079 mL/min/g, slightly lower than that in infant (0.0097 and 0.0104 mL/min/g) and adolescent (0.0097 and 0.0098 mL/min/g) monkeys. Conclusion: These results suggest that P-gp function in the BBB changes with development in rhesus monkeys, and this change may be closely related to the observed difference in drug responses in the brains of children and adult humans.

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In Vivo Evaluation of P-glycoprotein Function at the Blood-Brain Barrier in Nonhuman Primates Using [¹¹C]Verapamil

Cited by 80 publications

References 30 publications

Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies

Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies

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

Developmental Changes in P-Glycoprotein Function in the Blood–Brain Barrier of Nonhuman Primates: PET Study with R-¹¹C-Verapamil and ¹¹C-Oseltamivir

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In Vivo Evaluation of P-glycoprotein Function at the Blood-Brain Barrier in Nonhuman Primates Using [11C]Verapamil

Cited by 80 publications

References 30 publications

Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies

Modest Effect of Impaired P-glycoprotein on the Plasma Concentrations of Fexofenadine, Quinidine, and Loperamide following Oral Administration in Collies

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

Developmental Changes in P-Glycoprotein Function in the Blood–Brain Barrier of Nonhuman Primates: PET Study with R-11C-Verapamil and 11C-Oseltamivir

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In Vivo Evaluation of P-glycoprotein Function at the Blood-Brain Barrier in Nonhuman Primates Using [¹¹C]Verapamil

Developmental Changes in P-Glycoprotein Function in the Blood–Brain Barrier of Nonhuman Primates: PET Study with R-¹¹C-Verapamil and ¹¹C-Oseltamivir