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Zobrist, R. Howard; Quan, Danyi; Thomas, Heather; Stanworth, Stephanie H.; Sanders, Steven W.

doi:10.1023/a:1022259011052

Cited by 67 publications

(17 citation statements)

References 15 publications

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“…This was also observed in human plasma after the system removal. 24) There have been no data available for this phenomenon, however, stimulation as a result of the removal could be one of the causes of this increase. However, it is not considered that the increase in receptor occupancy influences the effect in the bladder because the increase is relatively small.…”

Section: Discussionmentioning

confidence: 99%

“…All the compounds were dissolved in saline. (R/S)-OXY transdermal delivery systems (12,24 and 48 mg/body as a free base) were applied for 48 h on the shaved backs of the rats after anesthetization with diethyl ether. Blood samples with heparin were collected via the tail vein after administration and centrifuged immediately.…”

Section: Pharmacokinetics/pharmacodynamics Analysis Of the Relationshmentioning

confidence: 99%

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Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

Mizushima

Kinoshita

Abe

et al. 2007

Biological & Pharmaceutical Bulletin

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Oxybutynin ((R/S)-OXY) is an anticholinergic compound widely used by overactive bladder patients with symptoms of urge urinary incontinence 1,2) and several formulations with different pharmacokinetics (PK) profiles of (R/S)-OXY are available in the market. (R/S)-OXY and (R/S)-N-desethyloxybutynin ((R/S)-DEOB), a pharmacologically active metabolite of (R/S)-OXY, inhibit muscarinic acetylcholine receptors in the bladder, especially antagonizing M 2 and M 3 receptors, which mainly mediate direct contractile response in the bladder 3) and the affinities of both compounds for M 3 receptors are higher than those for M 2 receptors. 4,5) Both (R/S)-OXY and (R/S)-DEOB have an asymmetric carbon, and the (R)-enantiomers ((R)-OXY and (R)-DEOB, respectively) have an antimuscarinic effect on the bladder smooth muscle greater than their corresponding (S)-enantiomers ((S)-OXY and (S)-DEOB, respectively).6,7) Although several reports have evaluated the relationships between PK exposure and antimuscarinic effects after the administration of (R/S)-OXY, 3,[8][9][10][11][12][13] most of them were not focused on the binding to muscarinic receptors, the competition of (R/S)-DEOB with (R/S)-OXY for the muscarinic receptor binding sites or the difference of potency between (R)-and (S)-enantiomers. In addition, there are few reports elucidating the receptor occupancy to show suitable pharmacological effects of (R)-OXY and (R)-DEOB.For compounds which bind internal receptors such as histamine H 1 receptor, dopamine receptors, muscarinic receptors, the occupancies of these receptors were extensively examined in order to discover the PK/pharmacodynamic (PD) relationship in the target sites and to determine the appropriate receptor occupancies for their pharmacological effects, including their efficacies and side effects.14-18) These correlations between the receptor occupancies and the PD/safety parameters would be useful to optimize the dose regimen and formulation. 19) In the studies, positron emission tomography (PET) 14,15) and the receptor occupancy theory [16][17][18] were used for measuring or predicting the receptor occupancy. PET studies have an advantage in that they can measure the receptor occupancy directly, however, the synthesis of the positron emission substrate and the system of detection are sometimes impediments to conducting a study. On the other hand, the receptor occupancy theory is known as a useful method to predict receptor-mediated pharmacological actions by quantitatively calculating the receptor occupancy of a drug at a target receptor with free plasma concentrations of the drug. This theory has been successfully applied to adrenergic receptors, serotonin 5-HT receptors, dopamine D 2 receptors, histamine H 1 receptors, muscarinic acetylcholine receptors and so on. [16][17][18] Thus, to understand the PK/PD relationship of (R/S)-OXY and (R/S)-DEOB, the PK of the enantiomers of (R/S)-OXY and (R/S)-DEOB after intravenous (i.v.), oral (p.o.) and transdermal administrations and the unbound fractions in plasma were ex...

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Section: Discussionmentioning

confidence: 99%

Section: Pharmacokinetics/pharmacodynamics Analysis Of the Relationshmentioning

confidence: 99%

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

Mizushima

Kinoshita

Abe

et al. 2007

Biological & Pharmaceutical Bulletin

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“…Under this incubation condition K m of 9.3 and 7.9 nmol L −1 for (R)-OXY and (S)-OXY, respectively, were observed indicating greater enzyme affinity to (S)-OXY and consequently, the enantioselective OXY biotransformation by rat liver microsomes. Previous studies have clearly demonstrated the enantioselective pharmacokinetic characteristics of OXY and DEO after oral or transdermal administration in man [5,6], however only one recent report described the in vitro stereoselective biotransformation of OXY using human microsomal fraction [9] as well as recombinant human P450-expressing microsomes. Comparing our preliminary results with those reported by Mizushima et al [9], the R/S ratio K m of OXY is similar in human and rat microsomes.…”

Section: Methods Applicationmentioning

confidence: 99%

“…DEO is present in the plasma at concentrations approximately 4-10 times higher than those of the parent compound and it has similar anticholinergic effects of OXY. In therapeutic use, DEO seems to contribute greatly to the anticholinergic side effects, in particular dry mouth [5,6]. The possibility of OXY delivering via non-oral route may be a more effective method of reducing the drug adverse reactions.…”

Section: Oxybutyninmentioning

confidence: 99%

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Enantioselective analysis of oxybutynin and N-desethyloxybutynin with application to an in vitro biotransformation study☆

Fonseca

Freitas

Pinto

et al. 2008

Journal of Chromatography B

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Simultaneous quantification of oxybutynin and its active metabolite N‐desethyl oxybutynin in rat plasma by ultra‐high‐performance liquid chromatography–tandem mass spectrometry and its application in a pharmacokinetic study of oxybutynin transdermal patch

Tian

Wen

Sun

et al. 2018

Biomedical Chromatography

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A rapid, selective and sensitive ultra‐high‐performance liquid chromatography–tandem mass spectrometry method was developed to simultaneously determine oxybutynin and its active metabolite N‐desethyl oxybutynin in rat plasma. A 0.1 mL sample of plasma was extracted with n‐hexane. Chromatographic separation was performed on a UPLC BEH C18 column (2.1 × 100 mm i.d.,1.7 μm) with mobile phase of methanol–water (containing 2 mmol/L ammonium acetate and 0.1% formic acid; 90:10, v/v). The detection was performed in positive selected reaction monitoring mode. Each plasma sample was chromatographed within 3 min. The linear calibration curves were obtained in the concentration range of 0.0944–189 ng/mL (r ≥ 0.99) for oxybutynin and 0.226–18.0 ng/mL (r ≥ 0.99) for N‐desethyl oxybutynin. The intra‐ and inter‐day precision (relative standard deviation) values were not more than 14% and the accuracy (relative error) was within ±7.6%. The method described was superior to previous methods for the quantitation of oxybutynin with three product ions and was successfully applied to a pharmacokinetic study of oxybutynin and its active metabolite N‐desethyl oxybutynin in rat plasma after transdermal administration.

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Untitled

Cited by 67 publications

References 15 publications

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats

Enantioselective analysis of oxybutynin and N-desethyloxybutynin with application to an in vitro biotransformation study☆

Simultaneous quantification of oxybutynin and its active metabolite N‐desethyl oxybutynin in rat plasma by ultra‐high‐performance liquid chromatography–tandem mass spectrometry and its application in a pharmacokinetic study of oxybutynin transdermal patch

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