Pharmacokinetics of Atenolol Enantiomers in Humans and Rats

Mehvar, Reza; Gross, Mary E.; Kreamer, R.

doi:10.1002/jps.2600791007

Cited by 58 publications

(36 citation statements)

References 21 publications

(4 reference statements)

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“…5; Table 3). Our in vitro data are in agreement with clinical observations showing little to a very small difference in the renal clearance of R-and S-atenolol (Boyd et al, 1989;Mehvar et al, 1990). To date, very few studies reported a stereoselective interaction of organic cations with hOCTs or hMATEs (Zhou et al, 2014).…”

Section: Discussionsupporting

confidence: 91%

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

et al. 2015

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Atenolol is a b-blocker widely used in the treatment of hypertension. Atenolol is cleared predominantly by the kidney by both glomerular filtration and active secretion, but the molecular mechanisms involved in its renal secretion are unclear. Using a panel of human embryonic kidney cell lines stably expressing human organic cation transporter (hOCT) 1-3, human organic anion transporter (hOAT) 1, hOAT3, human multidrug and toxin extrusion protein (hMATE) 1, and hMATE2-K, we found that atenolol interacted with both organic cation and anion transporters. However, it is transported by hOCT1, hOCT2, hMATE1, and hMATE2-K, but not by hOCT3, hOAT1, and hOAT3. A detailed kinetic analysis coupled with absolute quantification of membrane transporter proteins by liquid chromatographytandem mass spectrometry revealed that atenolol is an excellent substrate for the renal transporters hOCT2, hMATE1, and hMATE2-K. The K m values for hOCT2, hMATE1, and hMATE2-K are 280 6 4, 32 6 5, and 76 6 14 mM, respectively, and the calculated turnover numbers are 2.76, 0.41, and 2.20 s 21 , respectively. To demonstrate unidirectional transepithelial transport of atenolol, we developed and functionally validated a hOCT2/hMATE1 double-transfected Madin-Darby canine kidney cell culture model. Transwell studies showed that atenolol transport in the basal (B)-to-apical (A) direction is 27-fold higher than in the A-to-B direction, whereas its B-to-A/A-to-B transport ratio was only 2 in the vectortransfected control cells. The overall permeability of atenolol in the B-to-A direction in hOCT2/hMATE1 cells was 44-fold higher than in control cells. Together, our data support that atenolol tubular secretion is mediated through the hOCT2/hMATEs secretion pathway and suggest a significant role of organic cation transporters in the disposition of an important antihypertensive drug.

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Section: Discussionsupporting

confidence: 91%

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

et al. 2015

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“…In plasma, concentrations of ðÀÞ enantiomer exceeded those of ðþÞ enantiomer [29]. The data from this in vitro study matched the pharmacokinetic data of the drug in the rat, in which ðÀÞ enantiomer attained higher plasma concentrations than antipode [30].…”

Section: Distributionsupporting

confidence: 69%

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Brocks

2006

Biopharm. Drug Dispos.

134

108

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Many marketed drugs are chiral and are administered as the racemate, a 50:50 combination of two enantiomers. Pharmacodynamic and pharmacokinetic differences between enantiomers are well documented. Because of enantioselectivity in pharmacokinetics, results of in vitro pharmacodynamic studies involving enantiomers may differ from those in vivo where pharmacokinetic processes will proceed. With respect to pharmacokinetics, disparate plasma concentration vs time curves of enantiomers may result from the pharmacokinetic processes proceeding at different rates for the two enantiomers. At their foundation, pharmacokinetic processes may be enantioselective at the levels of drug absorption, distribution, metabolism and excretion. In some circumstances, one enantiomer can be chemically or biochemically inverted to its antipode in a unidirectional or bidirectional manner. Genetic consideration such as polymorphic drug metabolism and gender, and patient factors such as age, disease state and concomitant drug intake can all play a role in determining the relative plasma concentrations of the enantiomers of a racemic drug. The use of a nonstereoselective assay method for a racemic compound can lead to difficulties in interpretation of data from, for example, bioequivalence or dose/concentration vs effect assessments. In this review data from a number of representative studies involving pharmacokinetics of chiral drugs are presented and discussed.

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“…The PK parameters obtained from the description of the profiles by a three-compartment model are comparable with literature (Mehvar et al, 1990;Belpaire et al, 1993;de Lange et al, 1994). However, in the literature, the plasma concentrations of atenolol after i.v.…”

Section: Discussionsupporting

confidence: 81%

Mechanism-Based Pharmacodynamic Modeling ofS(–)-Atenolol: Estimation of in Vivo Affinity for the β₁-Adrenoceptor with an Agonist-Antagonist Interaction Model

Steeg¹,

Freijer²,

Danhof³

et al. 2007

J Pharmacol Exp Ther

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The aim of this study was the development of an agonistantagonist interaction model to estimate the in vivo affinity of S(Ϫ)-atenolol for the ␤ 1 -adrenoreceptor. Male Wistar-Kyoto (WKY) rats were used to characterize the interaction between the model drugs isoprenaline (to induce tachycardia) and S(Ϫ)-atenolol. Blood samples were taken to determine plasma pharmacokinetics. Reduction of isoprenaline-induced tachycardia was used as a pharmacodynamic endpoint. The pharmacokinetic-pharmacodynamic relationship of isoprenaline was first characterized with the operational model of agonism using the literature value for the affinity (K A ) of isoprenaline (3.2 ϫ 10 Ϫ8 M; left atria WKY rats). Resulting estimates for baseline (E 0 ), maximal effect (E max ), and efficacy () were 374 (1.9%), 130 (5.9%), and 247 (33%) beats per minute, respectively. In addition, the interaction between isoprenaline and S(Ϫ)-atenolol was characterized using a pharmacodynamic interaction model based on the operational model of agonism that describes the heart rate response based on the affinity of the agonist (K A ), the affinity of the antagonist (K B ), the efficacy (), the maximal effect (E max ), the Hill coefficient (n H ), the concentrations of isoprenaline and atenolol, and the displacement of the endogenous agonist adrenaline. The estimated in vivo affinity (K B ) of S(Ϫ)-atenolol for the ␤ 1 -receptor was 4.6 ϫ 10 Ϫ8 M. The obtained estimate for in vivo affinity of S(Ϫ)-atenolol (4.6 ϫ 10 Ϫ8 M) is comparable to literature values for the in vitro affinity in functional assays. In conclusion, a meaningful estimate of in vivo affinity for S(Ϫ)-atenolol could be obtained using a mechanismbased pharmacodynamic modeling approach.The concentration-effect relationships of agonists depend on a combination of the binding to the target (affinity) and the efficiency in activating the target (intrinsic efficacy). In contrast, the activity of a pure antagonist depends solely on binding because it results from the displacement of the (endogenous) agonist from the target (Hardman et al., 2001). Although in theory the mechanism of action of antagonists is less complex than that of agonists, the characterization and quantification of the pharmacological effect of antagonists in vivo is challenging; it requires not only information on concentration of the antagonist but also on the concentration and the intrinsic efficacy of the agonist(s) to be replaced from the target (Kenakin, 1993).In drug development, in vitro binding studies are typically performed to characterize the association between the new chemical entity and receptor by its ability to displace the radioligand at various concentrations (Sweetnam et al., 1993). Quantitative analysis of the displacement curve yields estimates of the affinity of the drug, which is usually represented as the equilibrium dissociation constant (K D ) (Copeland et al., 2006). In functional studies, the affinity of an antagonist can be obtained from a functional assay (i.e., cAMP accumulation) using the d...

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Pharmacokinetics of Atenolol Enantiomers in Humans and Rats

Cited by 58 publications

References 21 publications

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Mechanism-Based Pharmacodynamic Modeling ofS(–)-Atenolol: Estimation of in Vivo Affinity for the β₁-Adrenoceptor with an Agonist-Antagonist Interaction Model

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Pharmacokinetics of Atenolol Enantiomers in Humans and Rats

Cited by 58 publications

References 21 publications

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Mechanism-Based Pharmacodynamic Modeling ofS(–)-Atenolol: Estimation of in Vivo Affinity for the β1-Adrenoceptor with an Agonist-Antagonist Interaction Model

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Mechanism-Based Pharmacodynamic Modeling ofS(–)-Atenolol: Estimation of in Vivo Affinity for the β₁-Adrenoceptor with an Agonist-Antagonist Interaction Model