Noninvasive evaluation of brain muscarinic receptor occupancy of oxybutynin, darifenacin and imidafenacin in rats by positron emission tomography

Yoshida, Akira; Maruyama, Shuji; Fukumoto, Dai; Tsukada, Hideo; Ito, Yoshihiko; Yamada, Shizuo

doi:10.1016/j.lfs.2010.06.008

Cited by 28 publications

(30 citation statements)

References 27 publications

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“…It was shown that oral imidafenacin (0.79, 1.57, and 6.26 mol/kg) had little effect on binding parameters in the rat brain, whereas oxybutynin bound significantly to muscarinic receptors. Our recent results with autoradiography and positron emission tomography have shown that intravenous injection of oxybutynin but not imidafenacin binds significantly to muscarinic receptors in the rat brain (Yoshida et al, 2010b). In agreement with these findings, imidafenacin at similar doses did not affect escape latency in the Morris water maze task, suggesting little effect on spatial learning and memory (Kobayashi et al, 2007b).…”

Section: Discussionsupporting

confidence: 73%

Selective Binding of Bladder Muscarinic Receptors in Relation to the Pharmacokinetics of a Novel Antimuscarinic Agent, Imidafenacin, to Treat Overactive Bladder

Yamada¹,

Seki²,

Ogoda³

et al. 2010

J Pharmacol Exp Ther

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The binding of orally administered imidafenacin, used to treat overactive bladders, to muscarinic receptors in rat tissue was characterized based on pharmacokinetics. The binding in six tissues including bladder tissue was measured using [N-methyl-3 H] scopolamine methyl chloride ([ 3 H]NMS). Pharmacokinetic parameters were estimated from measurements of the concentration of imidafenacin in serum, the bladder, and the submaxillary gland by liquid chromatography-mass spectrometry/mass spectrometry. The receptor binding affinity of imidafenacin in vitro was significantly lower in the bladder than submaxillary gland or colon. The oral administration of imidafenacin (0.79, 1.57, and 6.26 mol/kg) was characterized by a more selective and longer-lasting binding to muscarinic receptors in the bladder than other tissues. Imidafenacin showed little binding to brain muscarinic receptors, consistent with its minor effect on the central nervous system. Pharmacokinetic data showed that orally administered imidafenacin was distributed at a higher concentration in the bladder than the serum or submaxillary gland of rats. After the intravesical instillation of imidafenacin, there was significant binding of muscarinic receptors in the bladder. Furthermore, a significant level of imidafenacin was detected in the urine of rats given a 1.57 mol/kg concentration of this agent. The present study demonstrated that imidafenacin administered orally distributes predominantly to the bladder and exerts more selective and longer-lasting effect on the bladder than other tissues, such as the submaxillary gland, colon, and brain. Furthermore, the imidafenacin excreted in urine may play an important role in pharmacokinetic and pharmacological selectivity.

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Section: Discussionsupporting

confidence: 73%

Selective Binding of Bladder Muscarinic Receptors in Relation to the Pharmacokinetics of a Novel Antimuscarinic Agent, Imidafenacin, to Treat Overactive Bladder

Yamada¹,

Seki²,

Ogoda³

et al. 2010

J Pharmacol Exp Ther

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“…Yoshida et al [63] noninvasively characterized muscarinic receptor occupancy in rat brain after the systemic injection of imidafanacin, oxybutynin, and darifenacin by PET. The intravenous injection of oxybutynin but not imidafenacin or darifenacin at pharmacological doses decreased the binding potential of [ 11 C](+)3-MPB in the cerebral cortex and corpus striatum in a dose-dependent manner (Fig.…”

Section: Brain Muscarinic Receptor Binding Evaluated By Positron Emismentioning

confidence: 99%

Characterization of Bladder Selectivity of Antimuscarinic Agents on the Basis ofIn VivoDrug-Receptor Binding

et al. 2012

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The in vivo muscarinic receptor binding of antimuscarinic agents (oxybutynin, solifenacin, tolterodine, and imidafenacin) used to treat urinary dysfunction in patients with overactive bladder is reviewed. Transdermal administration of oxybutynin in rats leads to significant binding of muscarinic receptors in the bladder without long-term binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin shows significant and long-lasting binding to muscarinic receptors in mouse tissues expressing the M3 subtype. Oral tolterodine binds more selectively to muscarinic receptors in the bladder than in the submaxillary gland in mice. The muscarinic receptor binding of oral imidafenacin in rats is more selective and longer-lasting in the bladder than in other tissues such as the submaxillary gland, heart, colon, lung, and brain, suggesting preferential muscarinic receptor binding in the bladder. In vivo quantitative autoradiography with (+)N-[11C]methyl-3-piperidyl benzilate in rats shows significant occupancy of brain muscarinic receptors with the intravenous injection of oxybutynin, solifenacin, and tolterodine. The estimated in vivo selectivity in brain is significantly greater for solifenacin and tolterodine than for oxybutynin. Imidafenacin occupies few brain muscarinic receptors. Similar findings for oral oxybutynin were observed with positron emission tomography in conscious rhesus monkeys with a significant disturbance of short-term memory. The newer generation of antimuscarinic agents may be advantageous in terms of bladder selectivity after systemic administration.

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“…Literature survey reveals that there are few methods reported for quantitation and identification of darifenacin in pharmaceutical formulations [6][7][8][9][10][11][12][13][14][15] and biological matrices [16][17][18][19][20]. These methods are developed with different analytical instruments like UV [7,8], spectroflurimetric [9], HPTLC [10], HPLC [11][12][13][14], LC-MS [15,19,20], and positron emission tomography [16].…”

Section: Introductionmentioning

confidence: 99%

“…These methods are developed with different analytical instruments like UV [7,8], spectroflurimetric [9], HPTLC [10], HPLC [11][12][13][14], LC-MS [15,19,20], and positron emission tomography [16]. Among all the reported methods quantification in rats [16], mice [18], and human plasma [19,20] methods are helpful for clinical pharmacokinetics. The reported methods [16,[18][19][20] do not show the accurate and rugged method.…”

Section: Introductionmentioning

confidence: 99%

“…Among all the reported methods quantification in rats [16], mice [18], and human plasma [19,20] methods are helpful for clinical pharmacokinetics. The reported methods [16,[18][19][20] do not show the accurate and rugged method. It is required to develop and validate the most economical, simple, rugged, and reproducible bioanalytical method for quantification of darifenacin in biological matrices for its clinical pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

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Method Development and Validation of Darifenacin in Rat Plasma by Liquid Chromatography-Tandem Mass Spectrometry: Application to a Pharmacokinetic Study

Karavadi

Challa²

2012

ISRN Spectroscopy

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A selective, sensitive, and high-throughput liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) method has been developed and validated for the quantitation of darifenacin in rat plasma. Sample clean up involved liquid-liquid extraction (LLE) and used 100 µL of rat plasma. Zorbax, SB C18, 4.6 × 75 mm, 3.5 µm particle size analytical column using 10 mM ammonium acetate buffer (pH 5) and methanol (10 : 90, v/v) as the mobile phase was used. The parent → product ion transitions for the drug (m/z 427.3 → 147.3) and IS (m/z 431.4 → 151.2) were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring (MRM) and positive ion mode. The method was validated over the concentration range of 10.00-20000.00 pg/mL for darifenacin. The method was successfully applied into a pharmacokinetic study in rat plasma under fasting conditions.

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Noninvasive evaluation of brain muscarinic receptor occupancy of oxybutynin, darifenacin and imidafenacin in rats by positron emission tomography

Cited by 28 publications

References 27 publications

Selective Binding of Bladder Muscarinic Receptors in Relation to the Pharmacokinetics of a Novel Antimuscarinic Agent, Imidafenacin, to Treat Overactive Bladder

Selective Binding of Bladder Muscarinic Receptors in Relation to the Pharmacokinetics of a Novel Antimuscarinic Agent, Imidafenacin, to Treat Overactive Bladder

Characterization of Bladder Selectivity of Antimuscarinic Agents on the Basis ofIn VivoDrug-Receptor Binding

Method Development and Validation of Darifenacin in Rat Plasma by Liquid Chromatography-Tandem Mass Spectrometry: Application to a Pharmacokinetic Study

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