Receptor occupancy in lumbar CSF as a measure of the antagonist activity of atenolol, metoprolol and propranolol in the CNS.

Kaila, Timo; Marttila, Reijo J.

doi:10.1111/j.1365-2125.1993.tb04177.x

Cited by 11 publications

(14 citation statements)

References 30 publications

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“…order to obtain the best fit for the estimates of K D and K i. The values obtained (Table 1) were in conformity with those reported in the literature [9,11,13,14].…”

Section: Methodssupporting

confidence: 75%

“…The intra-assay coefficient of variation (CV) was 11% at the detection limit of 6 ng-ml-1. The//1-adrenoceptor-binding component of metoprolol was analysed by using a//1-subtype-specific radioreceptor assay, as described elsewhere [9,10]. The sensitivity for metoprolol in plasma was 3.8 ng.…”

Section: Metoprolol Concentrationsmentioning

confidence: 99%

“…The Ki-values of R,S-metoprolol and R,S-4-OH-metoprolol (Astra, SOdert~ilje, Sweden) were determined by displacing the radioligand from//-adrenoceptor sites in the membranes, as previously described [9,10]. The binding isotherms were analysed using LIGAND [18,19] in…”

Section: Ko-and Ki-valuesmentioning

confidence: 99%

“…In addition, because the extent of receptor occupancy is closely related to the intensity of receptor-blockade, receptor-binding assays might also offer a basis for constructing pharmacodynamic models of bioequivalence [5]. In this study, we administered two different formulations of metoprolol to healthy volunteers and determined the relative bioavailability of R,S-metoprolol and its illreceptor binding-component, and assessed the extent to which the active drug moiety in plasma samples occupied rabbit lung ill-and rat reticulocyte fl2-adrenoceptors at intervals after drug intake [9,10].…”

mentioning

confidence: 99%

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Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties

Kaila

Roivas

Neuvonen

1994

Eur J Clin Pharmacol

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The bioavailability and pharmacodynamic bioequivalence of a conventional and an experimental sustained-release formulation of 100 mg metoprolol tartrate were studied in a randomised cross-over study in seven healthy volunteers by assessing over 24 h the plasma kinetics of R,S-metoprolol, its beta 1-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors. The formulations differed markedly in their kinetic characteristics: the peak plasma concentration (Cmax) of R,S-metoprolol after administration of the conventional formulation was 140 ng.ml-1, (n = 7) and it was approximately one-third of that after the sustained-release formulation, 49 ng.ml-1, (n = 6); the AUC0-24 h-values for the formulations were 700 and 310 ng.h.ml-1, respectively. The Cmax for the beta 1-adrenoceptor binding component of metoprolol was 180 ng.ml-1 (n = 7) after administration of the conventional, and 74 ng.ml-1 after administration of the sustained-release formulation. The corresponding AUC0-24 h-values for the receptor binding component were 920 and 470 ng.h.ml-1 (n = 7). Thus, the kinetic differences between R,S-metoprolol and the beta 1-receptor binding component were considerable and they were affected by the type of formulation. In general, after administration of the sustained-release formulation, the percentage beta 1- and beta 2-adrenoceptor occupancy of metoprolol in plasma was 5-15% less than after administration of the conventional formulation.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…order to obtain the best fit for the estimates of K D and K i. The values obtained (Table 1) were in conformity with those reported in the literature [9,11,13,14].…”

Section: Methodssupporting

confidence: 75%

Section: Metoprolol Concentrationsmentioning

confidence: 99%

Section: Ko-and Ki-valuesmentioning

confidence: 99%

mentioning

confidence: 99%

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Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties

Kaila

Roivas

Neuvonen

1994

Eur J Clin Pharmacol

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“…Besides physicochemical properties such as molecular size and lipophilicity, high beta(2)-receptor affinity has been proposed to be related to such effects [2]. Although the beta(1)-selective drugs, bisoprolol and metoprolol, have limited beta(2) affinity, sleep disturbances are stated as occurring “occasionally,” corresponding to a frequency of <1% [3,4].…”

Section: Introductionmentioning

confidence: 99%

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples

et al. 2017

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Background: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. Methods: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. Results: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. Conclusion: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.

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Extent of beta1- and beta2-receptor occupancy in plasma assesses the antagonist activity of metoprolol, pindolol, and propranolol in the elderly

Kaila

Iisalo

Lehtonen

et al. 1993

Cardiovasc Drug Ther

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We estimated antagonist activity of metoprolol, pindolol, and propranolol in elderly cardiovascular patients by determining the extent to which the drugs occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors in plasma samples during drug treatment. The randomized, double-blind, crossover study was carried out by administering twice daily 100 mg metoprolol, 5 mg pindolol, and 80 mg propranolol for 7 days to 20 hypertensive subjects with a mean age of about 70 years. A 2-week interval was kept between administration of the different regimens. Receptor occupancy was measured at 1 hour before and 2 hours after administration of the last dose of each regimen by adding rabbit lung beta 1- and rat reticulocyte beta 2-receptors to plasma samples and by labeling the receptors with a radiolabeled beta-antagonist, (-)-[3H]CGP-12177. The results and conclusions were the following: (a) The extent to which metoprolol, pindolol, and propranolol occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors in plasma samples estimated accurately the intensity of beta-receptor antagonism in the patients who did not tolerate physiological and pharmacological tests measuring the degree of beta 1- and beta 2-adrenoceptor blockade. (b) The mean beta 1- and beta 2-receptor occupancy of pindolol and propranolol varied between 76% and 99% during the treatments. The mean beta 1-receptor occupancy of the metoprolol regimen varied between 54% and 92%, and its beta 2-receptor occupancy varied between 6% and 38%. Thus the antagonist activity of the metoprolol regimen differed significantly from that of the other regimens (ANOVA for repeated measures, p < 0.05 and 0.001, for the beta 1- and beta 2-occupancy, respectively). (c) The extent of beta 1- and beta 2-receptor occupancy in plasma samples was in conformity with the literature on the intensity, selectivity, and duration of beta-blockade after similar drug doses. (d) The data on the receptor occupancy of beta-blocking drugs in plasma samples appear to be valuable in analyzing their effects, and it may be a method for optimizing drug therapy for aged cardiovascular patients.

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Receptor occupancy in lumbar CSF as a measure of the antagonist activity of atenolol, metoprolol and propranolol in the CNS.

Cited by 11 publications

References 30 publications

Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties

Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples

Extent of beta1- and beta2-receptor occupancy in plasma assesses the antagonist activity of metoprolol, pindolol, and propranolol in the elderly

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