***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: To investigate the effect of multiple‐dose  paroxetine intake on the stereoselective pharmacokinetics and the pharmacodynamics of metoprolol After administration of metoprolol , plasma concentrations of the drug are markedly higher in CYP2D6 poor metabolizers ( PMs ) than in non‐PMs . In a prospect i ve double‐blind 3‐month study , we investigated whether this translates into differences in  metoprolol  's effects after initiation of therapy . Despite administering equal doses to PMs and non‐PMs , metoprolol plasma concentrations were 4.9‐fold higher in the PM group . Metoprolol evoked significantly and persistently greater reductions in heart rate , diastolic blood pressure , and mean arterial pressure in PMs than in non‐PMs . It appears , therefore , that the CYP2D6 genotype contributes to interindividual differences in  metoprolol  response BACKGROUND AND OBJECTIVE Genetic polymorphism of CYP2D6 leads to differences in pharmacokinetics of CYP2D6 substrates . The CYP2D6 * 10 allele is clinical ly important in Koreans because of its high frequency in Asians . We investigated whether the pharmacokinetics of metoprolol was altered by the presence of the CYP2D6 * 10 allele in Korean subjects . METHODS One hundred and seven volunteers were recruited and grouped as CYP2D6 * 1/*1 , CYP2D6 * 1/*10 and CYP2D6 * 10/*10 according to their genotypes . Metoprolol tartrate 100 mg ( Betaloc ) was administered orally once to each subject in these three groups ( n = 6 , 7 and 5 , respectively ) . The pharmacokinetic parameters of metoprolol and its metabolite , alpha-hydroxymetoprolol , and the metabolic ratio for the three groups were estimated and compared . RESULTS AND DISCUSSION The area under the plasma concentration-time curve ( AUC(0 - ->infinity ) ) , the maximum plasma concentration ( C(max ) ) and the elimination half-life ( T(1/2 ) ) of metoprolol and alpha-hydroxymetoprolol for the CYP2D6 * 10/*10 group were all significantly different from those of the CYP2D6 * 1/*1 group ( P < 0.05 ) . The AUC(0 - ->infinity)s of metoprolol were 443.7 + /- 168.1 , 995.6 + /- 321.4 and 2545.3 + /- 632.0 ng.h/mL , and the AUC(0 - ->infinity)s of alpha-hydroxymetoprolol were 1232.0 + /- 311.2 , 1344.0 + /- 288.1 and 877.4 + /- 103.4 ng.h/mL for groups CYP2D6 * 1/*1 , * 1/*10 and * 10/*10 , respectively . The corresponding T(1/2 ) values of metoprolol were 2.7 + /- 0.5 , 3.2 + /- 1.3 and 5.0 + /- 1.1 h , while those of alpha-hydroxymetoprolol were 5.4+/-1.5 , 6.0 + /- 1.4 and 10.5 + /- 4.2 h , respectively . The metabolic ratios of the three groups were significantly different ( P < 0.05 ) . CONCLUSION The CYP2D6 * 10 allele altered the pharmacokinetics of metoprolol in Korean subjects and is likely to affect other drugs metabolized by the CYP2D6 enzyme , similarly AIMS Hydroxychloroquine ( HCQ ) is used widely in the treatment of chronic inflammatory diseases such as rheumatoid arthritis . Since there is great interindividual variability in the pharmacokinetics of HCQ and chloroquine is a potent inhibitor of CYP2D6-catalysed pathways in vitro , we wished to study the interaction of HCQ with CYP2D6-mediated metabolism of other drugs in vivo . METHODS Metoprolol and dextromethorphan ( DM ) were selected as probe drugs because they are well-studied and widely used test substrates of CYP2D6 . In this r and omized , double-blind crossover study , seven healthy volunteers with extensive metabolizer phenotype for CYP2D6 ingested either 400 mg hydroxychloroquine or placebo daily for 8 days after which single oral dose pharmacokinetics of metoprolol were investigated . Dextromethorphan metabolic ratio ( DM-MR ) was also determined at baseline and after the ingestion of HCQ or placebo . RESULTS Concomitant administration of HCQ increased the bioavailability of metoprolol , as indicated by significant increases in the area under the plasma concentration-time curve ( 65 + /- 4.6 % ) and maximal plasma concentrations ( 72 + /- 6.9 % ) of metoprolol . While the DM-MR values were not significantly changed , the phenotypic classification of one individual , who was heterozygous for a mutant CYP2D6 allele , was converted to a poor metabolizer by HCQ administration . CONCLUSIONS HCQ inhibits metoprolol metabolism most probably by inhibiting its biotransformation by CYP2D6 . The inhibitory effect of HCQ on dextromethorphan metabolism was not apparent when DM-MR was used as an indicator , except in an individual with limited CYP2D6 capacity BACKGROUND In patients with heart failure , beta-blockade has improved morbidity and left-ventricular function , but the impact on survival is uncertain . We investigated the efficacy of bisoprolol , a beta1 selective adrenoceptor blocker in decreasing all-cause mortality in chronic heart failure . METHODS In a multicentre double-blind r and omised placebo-controlled trial in Europe , we enrolled 2647 symptomatic patients in New York Heart Association class III or IV , with left-ventricular ejection fraction of 35 % or less receiving st and ard therapy with diuretics and inhibitors of angiotensin-converting enzyme .  We r and omly assigned patients bisoprolol 1.25 mg ( n=1327 ) or placebo ( n=1320 ) daily , the drug being progressively increased to a maximum of 10 mg per day . Patients were followed up for a mean of 1.3 years . Analysis was by intention to treat . FINDINGS CIBIS-II was stopped early , after the second interim analysis , because bisoprolol showed a significant mortality benefit . All-cause mortality was significantly lower with bisoprolol than on placebo ( 156 [ 11.8 % ] vs 228 [ 17.3 % ] deaths with a hazard ratio of 0.66 ( 95 % CI 0.54 - 0.81 , p<0.0001 ) . There were significantly fewer sudden deaths among patients on bisoprolol than in those on placebo ( 48 [ 3.6 % ] vs 83 [ 6.3 % ] deaths ) , with a hazard ratio of 0.56 ( 0.39 - 0.80 , p=0.0011 ) . Treatment effects were independent of the severity or cause of heart failure . INTERPRETATION Beta-blocker therapy had benefits for survival in stable heart-failure patients . Results should not , however , be extrapolated to patients with severe class IV symptoms and recent instability because safety and efficacy has not been established in these patients Premenopausal women may be most vulnerable to acute coronary syndromes at a point in their menstrual cycle when their plasma estrogen levels are the lowest during and immediately after menstruation . Metoprolol is a first-line drug in the management of patients with acute coronary syndrome ; however , when metoprolol was marketed in 1982 , women were largely excluded from clinical trials . Furthermore , the over-the-counter antihistamine diphenhydramine inhibited the metabolism of the CYP2D6 substrate metoprolol in healthy , young men with pharmacokinetic and pharmacodynamic consequences . The pharmacokinetics and pharmacodynamics of metoprolol  and its interaction with diphenhydramine  were investigated in a r and omized , double-blind , crossover , placebo-controlled manner in healthy , premenopausal extensive ( EM ; n = 16 ) and poor metabolizer ( PM ; n = 4 ) women immediately after menstruation . During the placebo phase , EMs had between 5.2- and 8.4-fold higher total clearance ( CL/F ) of R- and S-metoprolol compared with PMs , whereas the latter had a 35 % greater area under the effect curve ( AUEC ) and 60 % greater EC50 value for heart rate reduction than EMs ( all P < 0.05 ) .  Diphenhydramine coadmininstration caused a 2.2- to 3.2-fold decrease in CL/F of metoprolol enantiomers with a result ing 21 % increase in AUEC and 29 % increase in EC50 value for heart rate reduction in EMs ( all P < 0.05 ) . This is the first study to report an in-depth elucidation of metoprolol 's pharmacokinetics and hemodynamics in premenopausal EM and PM women at a point in their menstrual cycle when vulnerability for acute coronary events may be greatest . Caution is warranted when the over-the-counter antihistamine diphenhydramine is part of a chronic therapeutic regimen The prototype “ classic ” over‐the‐counter antihistamine diphenhydramine was shown to interact with the polymorphic P450 enzyme CYP2D6 . This project was undertaken to investigate ( 1 ) whether diphenhydramine inhibits the biotransformation of the clinical ly relevant CYP2D6 substrate metoprolol in vitro and ( 2 ) whether this in vitro interaction results in a clinical ly significant pharmacokinetic and pharmacodynamic drug interaction in vivo . In vitro incubations were carried out with microsomes obtained from lymphoblastic cells transfected with CYP2D6 complementary deoxyribonucleic acid to determine the type and extent of inhibition . We then r and omized 16 subjects with genetically determined high ( extensive metabolizers ) or low ( poor metabolizers ) CYP2D6 activity to receive  metoprolol ( 100 mg ) in the presence of steady‐state concentrations of diphenhydramine or placebo . In vitro , diphenhydramine was a potent competitive inhibitor of metoprolol α‐hydroxylation , exhibiting an inhibitory constant of 2 μmol/L and increasing the Michaelis‐Menten constant of metoprolol sixfold . In vivo , diphenhydramine  decreased metoprolol oral and nonrenal clearances twofold and metoprolol→α‐hydroxymetoprolol partial metabolic clearance 2.5‐fold in extensive metabolizers ( all P < .05 ) but not in poor metabolizers ( P > .2 ) . Although the hemodynamic response to metoprolol was unaltered by diphenhydramine in poor metabolizers ( P > .05 ) , metoprolol‐related effects on heart rate , systolic blood pressure , and Doppler‐derived aortic blood flow peak velocity were more pronounced and lasted significantly longer in extensive metabolizers receiving diphenhydramine compared with poor metabolizers and extensive metabolizers receiving placebo . We conclude that diphenhydramine inhibits the metabolism of metoprolol in extensive metabolizers , thereby prolonging the negative chronotropic and inotropic effects of the drug . Clinical ly relevant drug interactions may occur between diphenhydramine and many CYP2D6 substrates , particularly those with a narrow therapeutic index BACKGROUND Beta blockers reduce mortality in patients who have chronic heart failure , systolic dysfunction , and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors .  We aim ed to compare the effects of carvedilol and metoprolol on clinical outcome . METHODS In a multicentre , double-blind , and r and omised parallel group trial , we assigned 1511 patients with chronic heart failure to treatment with carvedilol ( target dose 25 mg twice daily ) and 1518 to metoprolol ( metoprolol tartrate , target dose 50 mg twice daily ) . Patients were required to have chronic heart failure ( NYHA II-IV ) , previous admission for a cardiovascular reason , an ejection fraction of less than 0.35 , and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated . The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission . Analysis was done by intention to treat . FINDINGS The mean study duration was 58 months ( SD 6 ) . The mean ejection fraction was 0.26 ( 0.07 ) and the mean age 62 years ( 11 ) . The all-cause mortality was 34 % ( 512 of 1511 ) for carvedilol and 40 % ( 600 of  
    Output:
    
This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer-specific metabolism of metoprolol