PubMed:1848636 JSONTXT

{"project":"LitCoin-sentences","denotations":[{"id":"T1","span":{"begin":0,"end":119},"obj":"Sentence"},{"id":"T2","span":{"begin":120,"end":242},"obj":"Sentence"},{"id":"T3","span":{"begin":243,"end":556},"obj":"Sentence"},{"id":"T4","span":{"begin":557,"end":649},"obj":"Sentence"},{"id":"T5","span":{"begin":650,"end":916},"obj":"Sentence"},{"id":"T6","span":{"begin":917,"end":988},"obj":"Sentence"},{"id":"T7","span":{"begin":989,"end":1074},"obj":"Sentence"},{"id":"T8","span":{"begin":1075,"end":1185},"obj":"Sentence"},{"id":"T9","span":{"begin":1186,"end":1400},"obj":"Sentence"},{"id":"T10","span":{"begin":1401,"end":1504},"obj":"Sentence"},{"id":"T11","span":{"begin":1505,"end":1625},"obj":"Sentence"},{"id":"T12","span":{"begin":1626,"end":1819},"obj":"Sentence"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

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The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"LitCoin-GeneOrGeneProduct-v0","denotations":[{"id":"T1","span":{"begin":52,"end":58},"obj":"GeneOrGeneProduct"},{"id":"T2","span":{"begin":59,"end":67},"obj":"GeneOrGeneProduct"},{"id":"T3","span":{"begin":158,"end":162},"obj":"GeneOrGeneProduct"},{"id":"T4","span":{"begin":163,"end":170},"obj":"GeneOrGeneProduct"},{"id":"T5","span":{"begin":273,"end":282},"obj":"GeneOrGeneProduct"},{"id":"T6","span":{"begin":390,"end":409},"obj":"GeneOrGeneProduct"},{"id":"T7","span":{"begin":410,"end":422},"obj":"GeneOrGeneProduct"},{"id":"T8","span":{"begin":511,"end":530},"obj":"GeneOrGeneProduct"},{"id":"T9","span":{"begin":629,"end":636},"obj":"GeneOrGeneProduct"},{"id":"T10","span":{"begin":751,"end":757},"obj":"GeneOrGeneProduct"},{"id":"T11","span":{"begin":803,"end":808},"obj":"GeneOrGeneProduct"},{"id":"T12","span":{"begin":817,"end":823},"obj":"GeneOrGeneProduct"},{"id":"T13","span":{"begin":897,"end":905},"obj":"GeneOrGeneProduct"},{"id":"T14","span":{"begin":938,"end":940},"obj":"GeneOrGeneProduct"},{"id":"T15","span":{"begin":1031,"end":1036},"obj":"GeneOrGeneProduct"},{"id":"T16","span":{"begin":1053,"end":1055},"obj":"GeneOrGeneProduct"},{"id":"T17","span":{"begin":1172,"end":1174},"obj":"GeneOrGeneProduct"},{"id":"T18","span":{"begin":1294,"end":1299},"obj":"GeneOrGeneProduct"},{"id":"T19","span":{"begin":1347,"end":1354},"obj":"GeneOrGeneProduct"},{"id":"T20","span":{"begin":1355,"end":1359},"obj":"GeneOrGeneProduct"},{"id":"T21","span":{"begin":1446,"end":1450},"obj":"GeneOrGeneProduct"},{"id":"T22","span":{"begin":1486,"end":1490},"obj":"GeneOrGeneProduct"},{"id":"T23","span":{"begin":1491,"end":1496},"obj":"GeneOrGeneProduct"},{"id":"T24","span":{"begin":1523,"end":1528},"obj":"GeneOrGeneProduct"},{"id":"T25","span":{"begin":1566,"end":1576},"obj":"GeneOrGeneProduct"},{"id":"T26","span":{"begin":1707,"end":1713},"obj":"GeneOrGeneProduct"},{"id":"T27","span":{"begin":1787,"end":1795},"obj":"GeneOrGeneProduct"},{"id":"T28","span":{"begin":1796,"end":1805},"obj":"GeneOrGeneProduct"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"LitCoin-GeneOrGeneProduct-v2","denotations":[{"id":"T1","span":{"begin":52,"end":58},"obj":"GeneOrGeneProduct"},{"id":"T2","span":{"begin":59,"end":67},"obj":"GeneOrGeneProduct"},{"id":"T3","span":{"begin":158,"end":162},"obj":"GeneOrGeneProduct"},{"id":"T4","span":{"begin":163,"end":170},"obj":"GeneOrGeneProduct"},{"id":"T5","span":{"begin":390,"end":409},"obj":"GeneOrGeneProduct"},{"id":"T6","span":{"begin":511,"end":530},"obj":"GeneOrGeneProduct"},{"id":"T7","span":{"begin":897,"end":905},"obj":"GeneOrGeneProduct"},{"id":"T8","span":{"begin":1294,"end":1299},"obj":"GeneOrGeneProduct"},{"id":"T9","span":{"begin":1347,"end":1354},"obj":"GeneOrGeneProduct"},{"id":"T10","span":{"begin":1446,"end":1450},"obj":"GeneOrGeneProduct"},{"id":"T11","span":{"begin":1523,"end":1528},"obj":"GeneOrGeneProduct"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"LitCoin-Disease-MeSH","denotations":[{"id":"T1","span":{"begin":637,"end":648},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"originalLabel","subj":"T1","obj":"D007008"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"LitCoin-GeneOrGeneProduct-v3","denotations":[{"id":"T1","span":{"begin":52,"end":58},"obj":"GeneOrGeneProduct"},{"id":"T2","span":{"begin":390,"end":409},"obj":"GeneOrGeneProduct"},{"id":"T3","span":{"begin":511,"end":530},"obj":"GeneOrGeneProduct"},{"id":"T4","span":{"begin":1294,"end":1299},"obj":"GeneOrGeneProduct"},{"id":"T5","span":{"begin":1347,"end":1354},"obj":"GeneOrGeneProduct"},{"id":"T6","span":{"begin":1523,"end":1528},"obj":"GeneOrGeneProduct"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"LitCoin_Mondo_095","denotations":[{"id":"T1","span":{"begin":284,"end":286},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T2","span":{"begin":311,"end":313},"obj":"DiseaseOrPhenotypicFeature"},{"id":"T4","span":{"begin":637,"end":648},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"mondo_id","subj":"T1","obj":"0006545"},{"id":"A2","pred":"mondo_id","subj":"T2","obj":"0019168"},{"id":"A3","pred":"mondo_id","subj":"T2","obj":"0019127"},{"id":"A4","pred":"mondo_id","subj":"T4","obj":"0003019"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"LitCoin-MeSH-Disease-2","denotations":[{"id":"T1","span":{"begin":637,"end":648},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"ID:","subj":"T1","obj":"D007008"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"LitCoin-MONDO_bioort2019","denotations":[{"id":"T1","span":{"begin":637,"end":648},"obj":"DiseaseOrPhenotypicFeature"}],"attributes":[{"id":"A1","pred":"#label","subj":"T1","obj":"D007008"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

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phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

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phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"bc5cdr-valid-experiment","denotations":[{"id":"T1","span":{"begin":0,"end":12},"obj":"Chemical"},{"id":"T2","span":{"begin":88,"end":98},"obj":"Chemical"},{"id":"T3","span":{"begin":171,"end":181},"obj":"Chemical"},{"id":"T4","span":{"begin":214,"end":226},"obj":"Chemical"},{"id":"T5","span":{"begin":227,"end":236},"obj":"Chemical"},{"id":"T6","span":{"begin":442,"end":452},"obj":"Chemical"},{"id":"T7","span":{"begin":545,"end":555},"obj":"Chemical"},{"id":"T8","span":{"begin":603,"end":613},"obj":"Chemical"},{"id":"T9","span":{"begin":617,"end":628},"obj":"Chemical"},{"id":"T10","span":{"begin":637,"end":648},"obj":"Disease"},{"id":"T11","span":{"begin":732,"end":742},"obj":"Chemical"},{"id":"T12","span":{"begin":838,"end":848},"obj":"Chemical"},{"id":"T13","span":{"begin":944,"end":955},"obj":"Chemical"},{"id":"T14","span":{"begin":1059,"end":1069},"obj":"Chemical"},{"id":"T15","span":{"begin":1149,"end":1160},"obj":"Chemical"},{"id":"T16","span":{"begin":1227,"end":1236},"obj":"Chemical"},{"id":"T17","span":{"begin":1238,"end":1249},"obj":"Chemical"},{"id":"T18","span":{"begin":1251,"end":1261},"obj":"Chemical"},{"id":"T19","span":{"begin":1294,"end":1317},"obj":"Chemical"},{"id":"T20","span":{"begin":1389,"end":1399},"obj":"Chemical"},{"id":"T21","span":{"begin":1409,"end":1419},"obj":"Chemical"},{"id":"T22","span":{"begin":1434,"end":1445},"obj":"Chemical"},{"id":"T23","span":{"begin":1512,"end":1522},"obj":"Chemical"},{"id":"T24","span":{"begin":1523,"end":1546},"obj":"Chemical"},{"id":"T25","span":{"begin":1652,"end":1662},"obj":"Chemical"},{"id":"T26","span":{"begin":1691,"end":1701},"obj":"Chemical"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"bc5cdr-valid-deepseek-nr-ng-experiment","denotations":[{"id":"T1","span":{"begin":0,"end":22},"obj":"Disease"},{"id":"T2","span":{"begin":88,"end":98},"obj":"Chemical"},{"id":"T3","span":{"begin":171,"end":181},"obj":"Chemical"},{"id":"T4","span":{"begin":214,"end":226},"obj":"Chemical"},{"id":"T5","span":{"begin":227,"end":236},"obj":"Chemical"},{"id":"T6","span":{"begin":442,"end":452},"obj":"Chemical"},{"id":"T7","span":{"begin":603,"end":613},"obj":"Chemical"},{"id":"T8","span":{"begin":617,"end":628},"obj":"Chemical"},{"id":"T9","span":{"begin":637,"end":648},"obj":"Disease"},{"id":"T10","span":{"begin":732,"end":742},"obj":"Chemical"},{"id":"T11","span":{"begin":838,"end":848},"obj":"Chemical"},{"id":"T12","span":{"begin":944,"end":955},"obj":"Chemical"},{"id":"T13","span":{"begin":1059,"end":1069},"obj":"Chemical"},{"id":"T14","span":{"begin":1294,"end":1317},"obj":"Chemical"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"bc5cdr-valid-deepseek-nr-g-experiment","denotations":[{"id":"T1","span":{"begin":0,"end":22},"obj":"Disease"},{"id":"T2","span":{"begin":88,"end":98},"obj":"Chemical"},{"id":"T3","span":{"begin":171,"end":181},"obj":"Chemical"},{"id":"T4","span":{"begin":214,"end":226},"obj":"Chemical"},{"id":"T5","span":{"begin":227,"end":236},"obj":"Chemical"},{"id":"T6","span":{"begin":442,"end":452},"obj":"Chemical"},{"id":"T7","span":{"begin":545,"end":555},"obj":"Chemical"},{"id":"T8","span":{"begin":603,"end":613},"obj":"Chemical"},{"id":"T9","span":{"begin":617,"end":628},"obj":"Chemical"},{"id":"T10","span":{"begin":637,"end":648},"obj":"Disease"},{"id":"T11","span":{"begin":732,"end":742},"obj":"Chemical"},{"id":"T12","span":{"begin":838,"end":848},"obj":"Chemical"},{"id":"T13","span":{"begin":1294,"end":1317},"obj":"Chemical"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"bc5cdr-valid-gpt-r-ng-experiment","denotations":[{"id":"T1","span":{"begin":0,"end":12},"obj":"Chemical"},{"id":"T2","span":{"begin":88,"end":98},"obj":"Chemical"},{"id":"T3","span":{"begin":171,"end":181},"obj":"Chemical"},{"id":"T4","span":{"begin":214,"end":226},"obj":"Chemical"},{"id":"T5","span":{"begin":227,"end":236},"obj":"Chemical"},{"id":"T6","span":{"begin":442,"end":452},"obj":"Chemical"},{"id":"T7","span":{"begin":545,"end":555},"obj":"Chemical"},{"id":"T8","span":{"begin":603,"end":613},"obj":"Chemical"},{"id":"T9","span":{"begin":617,"end":628},"obj":"Chemical"},{"id":"T10","span":{"begin":637,"end":648},"obj":"Disease"},{"id":"T11","span":{"begin":732,"end":742},"obj":"Chemical"},{"id":"T12","span":{"begin":838,"end":848},"obj":"Chemical"},{"id":"T13","span":{"begin":944,"end":955},"obj":"Chemical"},{"id":"T14","span":{"begin":1059,"end":1069},"obj":"Chemical"},{"id":"T15","span":{"begin":1149,"end":1160},"obj":"Chemical"},{"id":"T16","span":{"begin":1227,"end":1236},"obj":"Chemical"},{"id":"T17","span":{"begin":1238,"end":1249},"obj":"Chemical"},{"id":"T18","span":{"begin":1251,"end":1261},"obj":"Chemical"},{"id":"T19","span":{"begin":1294,"end":1317},"obj":"Chemical"},{"id":"T20","span":{"begin":1389,"end":1399},"obj":"Chemical"},{"id":"T21","span":{"begin":1434,"end":1445},"obj":"Chemical"},{"id":"T22","span":{"begin":1512,"end":1522},"obj":"Chemical"},{"id":"T23","span":{"begin":1523,"end":1546},"obj":"Chemical"},{"id":"T24","span":{"begin":1652,"end":1662},"obj":"Chemical"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"bc5cdr-valid-gpt-r-g-experiment","denotations":[{"id":"T1","span":{"begin":0,"end":12},"obj":"Chemical"},{"id":"T2","span":{"begin":88,"end":98},"obj":"Chemical"},{"id":"T3","span":{"begin":171,"end":181},"obj":"Chemical"},{"id":"T4","span":{"begin":214,"end":226},"obj":"Chemical"},{"id":"T5","span":{"begin":227,"end":236},"obj":"Chemical"},{"id":"T6","span":{"begin":442,"end":452},"obj":"Chemical"},{"id":"T7","span":{"begin":545,"end":555},"obj":"Chemical"},{"id":"T8","span":{"begin":603,"end":613},"obj":"Chemical"},{"id":"T9","span":{"begin":617,"end":628},"obj":"Chemical"},{"id":"T10","span":{"begin":637,"end":648},"obj":"Disease"},{"id":"T11","span":{"begin":732,"end":742},"obj":"Chemical"},{"id":"T12","span":{"begin":838,"end":848},"obj":"Chemical"},{"id":"T13","span":{"begin":944,"end":955},"obj":"Chemical"},{"id":"T14","span":{"begin":1059,"end":1069},"obj":"Chemical"},{"id":"T15","span":{"begin":1149,"end":1160},"obj":"Chemical"},{"id":"T16","span":{"begin":1227,"end":1236},"obj":"Chemical"},{"id":"T17","span":{"begin":1238,"end":1249},"obj":"Chemical"},{"id":"T18","span":{"begin":1251,"end":1261},"obj":"Chemical"},{"id":"T19","span":{"begin":1294,"end":1317},"obj":"Chemical"},{"id":"T20","span":{"begin":1389,"end":1399},"obj":"Chemical"},{"id":"T21","span":{"begin":1434,"end":1445},"obj":"Chemical"},{"id":"T22","span":{"begin":1512,"end":1522},"obj":"Chemical"},{"id":"T23","span":{"begin":1523,"end":1546},"obj":"Chemical"},{"id":"T24","span":{"begin":1652,"end":1662},"obj":"Chemical"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"bc5cdr-valid-gpt-r-m30","denotations":[{"id":"T1","span":{"begin":0,"end":12},"obj":"Chemical"},{"id":"T2","span":{"begin":88,"end":98},"obj":"Chemical"},{"id":"T3","span":{"begin":171,"end":181},"obj":"Chemical"},{"id":"T4","span":{"begin":214,"end":226},"obj":"Chemical"},{"id":"T5","span":{"begin":227,"end":236},"obj":"Chemical"},{"id":"T6","span":{"begin":442,"end":452},"obj":"Chemical"},{"id":"T7","span":{"begin":545,"end":555},"obj":"Chemical"},{"id":"T8","span":{"begin":603,"end":613},"obj":"Chemical"},{"id":"T9","span":{"begin":617,"end":628},"obj":"Chemical"},{"id":"T10","span":{"begin":637,"end":648},"obj":"Disease"},{"id":"T11","span":{"begin":732,"end":742},"obj":"Chemical"},{"id":"T12","span":{"begin":838,"end":848},"obj":"Chemical"},{"id":"T13","span":{"begin":944,"end":955},"obj":"Chemical"},{"id":"T14","span":{"begin":1059,"end":1069},"obj":"Chemical"},{"id":"T15","span":{"begin":1149,"end":1160},"obj":"Chemical"},{"id":"T16","span":{"begin":1227,"end":1236},"obj":"Chemical"},{"id":"T17","span":{"begin":1238,"end":1249},"obj":"Chemical"},{"id":"T18","span":{"begin":1251,"end":1261},"obj":"Chemical"},{"id":"T19","span":{"begin":1294,"end":1317},"obj":"Chemical"},{"id":"T20","span":{"begin":1389,"end":1399},"obj":"Chemical"},{"id":"T21","span":{"begin":1434,"end":1445},"obj":"Chemical"},{"id":"T22","span":{"begin":1512,"end":1522},"obj":"Chemical"},{"id":"T23","span":{"begin":1523,"end":1546},"obj":"Chemical"},{"id":"T24","span":{"begin":1652,"end":1662},"obj":"Chemical"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}

{"project":"bc5cdr-valid-gpt-r-m20","denotations":[{"id":"T1","span":{"begin":0,"end":12},"obj":"Chemical"},{"id":"T2","span":{"begin":88,"end":98},"obj":"Chemical"},{"id":"T3","span":{"begin":171,"end":181},"obj":"Chemical"},{"id":"T4","span":{"begin":214,"end":226},"obj":"Chemical"},{"id":"T5","span":{"begin":227,"end":236},"obj":"Chemical"},{"id":"T6","span":{"begin":442,"end":452},"obj":"Chemical"},{"id":"T7","span":{"begin":545,"end":555},"obj":"Chemical"},{"id":"T8","span":{"begin":603,"end":613},"obj":"Chemical"},{"id":"T9","span":{"begin":617,"end":628},"obj":"Chemical"},{"id":"T10","span":{"begin":637,"end":648},"obj":"Disease"},{"id":"T11","span":{"begin":732,"end":742},"obj":"Chemical"},{"id":"T12","span":{"begin":838,"end":848},"obj":"Chemical"},{"id":"T13","span":{"begin":944,"end":955},"obj":"Chemical"},{"id":"T14","span":{"begin":1059,"end":1069},"obj":"Chemical"},{"id":"T15","span":{"begin":1149,"end":1160},"obj":"Chemical"},{"id":"T16","span":{"begin":1227,"end":1236},"obj":"Chemical"},{"id":"T17","span":{"begin":1238,"end":1249},"obj":"Chemical"},{"id":"T18","span":{"begin":1251,"end":1261},"obj":"Chemical"},{"id":"T19","span":{"begin":1294,"end":1317},"obj":"Chemical"},{"id":"T20","span":{"begin":1389,"end":1399},"obj":"Chemical"},{"id":"T21","span":{"begin":1434,"end":1445},"obj":"Chemical"},{"id":"T22","span":{"begin":1512,"end":1522},"obj":"Chemical"},{"id":"T23","span":{"begin":1523,"end":1546},"obj":"Chemical"},{"id":"T24","span":{"begin":1652,"end":1662},"obj":"Chemical"}],"text":"Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.\nThe metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)"}