Biodistribution and metabolism of the anti-influenza drug [11C]oseltamivir and its active metabolite [11C]Ro 64-0802 in mice

Hatori, Akiko; Arai, Takuya; Yanamoto, Kazuhiko; Yamasaki, Tomoteru; Kawamura, Kazunori; Yui, Joji; Konno, Fujiko; Nakao, Ryuji; Suzuki, Kazutoshi; Zhang, Ming‐Rong

doi:10.1016/j.nucmedbio.2008.10.008

Cited by 27 publications

(27 citation statements)

References 25 publications

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“…In fact, intracerebroventricular injection of OCB for 1 day (0.3 g/mouse) alone increased ambulation. On the basis of this speculation, the production of OCB in the brain could be a key event that triggers the side effects in the central nervous system [9,11,16]. These data suggest that OCB may be related to increased locomotor activity (oseltamivir-induced behavioral changes) and our findings suggest an interaction between the central blockade of adenosine A 2 receptors by caffeine and OCB-induced behavioral changes.…”

Section: Discussionsupporting

confidence: 50%

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Effect of adenosine system in the action of oseltamivir on behavior in mice

Uchiyama

Hiromura

Shiratani

et al. 2015

Neuroscience Letters

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Section: Discussionsupporting

confidence: 50%

“…We referred to papers of [9] in the synthesis. An adenosine A 2 receptor antagonist, SCH58261 (Sigma Chemical Co.), and an adenosine A 2 receptor agonist, CGS21680 (Sigma Chemical Co.) were suspended in 3% carboxymethylcellulose (CMC) to which a few drops of Tween 80 had been added.…”

Section: Introductionmentioning

confidence: 99%

Effect of adenosine system in the action of oseltamivir on behavior in mice

Uchiyama

Hiromura

Shiratani

et al. 2015

Neuroscience Letters

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“…Hatori et al (37) examined the disposition of 11 C-oseltamivir in adult mice, but the brain concentration of 11 C-oseltamivir was below the limit of detection. Conversion of 11 C-oseltamivir to 11 C-Ro 64-0802 by carboxy esterase occurs more rapidly in adult mice than in adult monkeys, primarily because of differences in carboxy esterase activity in mouse and monkey serum.…”

Section: Discussionmentioning

confidence: 99%

“…We focused on oseltamivir; however, Ro 64-0802 is the major metabolite and is an active form of the drug that also penetrates the brain in mice with a low permeability, due to active efflux mediated by MRP4 (37,38). Ro 64-0802 is more potent than oseltamivir and causes neuronal excitability in rat hippocampal slices (39).…”

Section: Discussionmentioning

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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“…Indeed, Ose et al (2009) showed that transporters such as Mrp4 and Oat3 contribute to the active efflux of Ro 64-0802 at the BBB, and speculated that Oat3 is also involved in the brain uptake of Ro 64-0802, at least in mice. In addition, it has been demonstrated that mouse brain homogenate hydrolyzes 11 C-oseltamivir into Ro 64-0802 (Hatori et al, 2009). Although the in vitro enzymatic activity in mouse brain was 250-fold lower than that in plasma, it is possible that Ro64-0802 is formed and accumulated in brain, because its low lipophilicity would prevent diffusion across lipid bilayers.…”

Section: Discussionmentioning

confidence: 99%

Developmental changes of brain distribution and localization of oseltamivir and its active metabolite Ro 64-0802 in rats

et al. 2012

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INTRODUCTIONOseltamivir is an ester-type prodrug of the neuraminidase inhibitor [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (Ro 64-0802), which targets the A and B strains of influenza virus. This drug has been widely used in Japan and is stored on a large scale for use if an influenza pandemic occurs. However, there have been reports, though cases are rare, that infants and young patients taking oseltamivir have developed neuropsychiatric side effects, including mental instability and suicidal tendencies. Accordingly, The Ministry of Health, Labor and Welfare in Japan has restricted the use of this drug in teenagers and younger patients. The mechanisms of this putative side effect are not presently clear, though several studies have demonstrated that oseltamivir and Ro 64-0802 have an excitatory effect on hippocampal neurons (Izumi et al., 2007;Usami et al., 2008), a dopamine-releasing effect in the prefrontal cortex (Yoshino et al., 2008), and a hypothermia-promoting effect (Ono et al., 2008) in experimental animals.We have been studying the brain distribution of oseltamivir and Ro 64-0802 in animals (Morimoto et al., 2008). The distribution volume of Ro 64-0802 in the brain was equivalent to the vascular space. This suggested that the low lipophilicity of Ro 64-0802 (calculated clogP value of -0.97) restricts its penetration through the BBB by passive diffusion (Morimoto et al., 2008). On the other hand, the ester-type prodrug oseltamivir showed a more than ten-fold higher brain distribution compared with Ro 64-0802, reflecting its higher clogP value of 1.29. We have also demonstrated that the brain distribution of oseltamivir is limited by P-glycoprotein (P-gp)-mediated efflux transport at the blood-brain barrier: the brain concentration of oseltamivir in mdr1a/1b knockout mice was five-fold higher than that of wild-type mice (Morimoto et al., 2008 ABSTRACT -Oseltamivir, a prodrug of the neuraminidase inhibitor [3R, 4R, 5S]-4-Acetamide-5-amino-3-(1-ethylpropyl)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), is widely used for treatment of influenza infections in Japan, but may be associated with mental instability and suicidal tendencies as a rare side effect, especially in infants and young patients. We examined developmental changes in the brain distribution of oseltamivir and Ro 64-0802, and in the expression of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in rats by 8 weeks. Brain concentration and Kp ,app,brain (brain-to-plasma concentration ratio) of oseltamivir were highest in 2-week-old rats (1.45 μg/g brain and 0.14, respectively), and were negatively correlated with both age and P-gp expression at the BBB. In contrast, brain concentration and Kp ,app,brain of Ro 64-0802 after oral gavage of oseltamivir were lowest in 2-week-old rats (0.02 μg/g brain and 0.02), and increased with age. Mass imaging analysis revealed that both compounds were distributed homogenously in brain cross-sections, including the hippocampus. From these results, it was estim...

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Biodistribution and metabolism of the anti-influenza drug [11C]oseltamivir and its active metabolite [11C]Ro 64-0802 in mice

Cited by 27 publications

References 25 publications

Effect of adenosine system in the action of oseltamivir on behavior in mice

Effect of adenosine system in the action of oseltamivir on behavior in mice

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

Developmental changes of brain distribution and localization of oseltamivir and its active metabolite Ro 64-0802 in rats

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Biodistribution and metabolism of the anti-influenza drug [11C]oseltamivir and its active metabolite [11C]Ro 64-0802 in mice

Cited by 27 publications

References 25 publications

Effect of adenosine system in the action of oseltamivir on behavior in mice

Effect of adenosine system in the action of oseltamivir on behavior in mice

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

Developmental changes of brain distribution and localization of oseltamivir and its active metabolite Ro 64-0802 in rats

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