Plasma protein binding study of oxybutynin by high-performance frontal analysis

Shibukawa, Akimasa; Ishizawa, Nobuko; Kimura, Tomoko; Sakamoto, Yuki; Ogita, Kanae; Matsuo, Yuka; Kuroda, Yasuhisa; Matayatsuk, Chutima; Nakagawa, Terumichi; Wainer, Irving W.

doi:10.1016/s0378-4347(01)00497-2

Cited by 43 publications

(27 citation statements)

References 29 publications

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“…Unbound Fractions of the Enantiomers of OXY and DEOB in Rat Plasma The plasma unbound fractions of each enantiomer of OXY and DEOB were determined using the high-performance frontal analysis (HPFA) method described previously 20,21) with slight modifications. To 1980 ml rat plasma (nϭ3), 20 ml of methanol containing the test substance (final conc.…”

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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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: 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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“…This assumption was based on the fact that OXY, a strong base (pKa > 7), is predominantly bound to α 1 -acidglycoprotein (AGP), which is mainly located in the circulating plasma. Thus, the impact of OXY's binding to AGP within tissues was assumed to be minimal (82,90). Consequently, differences in OXY's volume of distribution can be mainly attributed to plasma protein-binding differences between the enantiomers (and racemic mixture), rather than to tissue binding (75,82,90).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the impact of OXY's binding to AGP within tissues was assumed to be minimal (82,90). Consequently, differences in OXY's volume of distribution can be mainly attributed to plasma protein-binding differences between the enantiomers (and racemic mixture), rather than to tissue binding (75,82,90). These differences were accommodated in the disposition model by using the enantiomer-specific f up value in the calculation of the K b , which in turn affects the volume of distribution (Eq.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that OXY enantiomers display stereo-selective pharmacokinetics, mainly attributable to differences in volume of distribution and clearance between the enantiomers (75). To overcome this issue, the aforementioned differences were accommodated into the mSAT model predictions, adapting OXY's parameters with the observed in vitro parameters for each enantiomer (75,82). For instance, changes in volume of distribution between enantiomers were mainly attributed to plasma protein-binding differences (75,82).…”

Section: Oxy's Oral Pk Simulations and Relative Bioavailability Predimentioning

confidence: 99%

“…To overcome this issue, the aforementioned differences were accommodated into the mSAT model predictions, adapting OXY's parameters with the observed in vitro parameters for each enantiomer (75,82). For instance, changes in volume of distribution between enantiomers were mainly attributed to plasma protein-binding differences (75,82). Hence, stereo-selective plasma protein binding was implemented in the model by employing the reported f up for each enantiomer (Table II).…”

Section: Oxy's Oral Pk Simulations and Relative Bioavailability Predimentioning

confidence: 99%

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Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

Olivares‐Morales

Ghosh

Aarons

et al. 2016

AAPS J

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Abstract.A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P eff,int ) to predict the regional gastrointestinal (GI) absorption (f abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin's modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F G ) rather than due to a higher colonic f abs , thus confirming previous hypotheses. The predicted f abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F G as the main factor responsible for the higher bioavailability of oxybutynin's OROS® formulation vs. the IR.

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Chiral Pharmaceuticals

Tiritan

Ribeiro

Fernandes

et al. 2016

Kirk-Othmer Encyclopedia of Chemical Technology

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The implication of chirality in pharmaceuticals is briefly reviewed, presenting the basic concepts and the chiral recognition phenomenon in biological systems. The importance to recognize enantiomers of chiral pharmaceuticals, both in pharmacology and environmental fields, is emphasized and many examples were selected to demonstrate the significance of chirality in both areas. Methodologies to obtain single enantiomers and to control the enantiomeric fraction associated with enantioseparation of chiral pharmaceuticals are also discussed. Several enantioselective methods using liquid chromatography (LC) with chiral stationary phases (CSPs) in biomedical and environmental fields are presented. The most used CSPs, their advantages and drawbacks, are swiftly revised.

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Plasma protein binding study of oxybutynin by high-performance frontal analysis

Cited by 43 publications

References 29 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

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

Chiral Pharmaceuticals

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