Writing committee me tions to which their s ply; see Appendix ACCF/AHATask Fo Surgeons Representa tative Heart Rhythm ography and Int Echocardiography Re ciety of America Rep resentative kkACCF/ Task Force member d This document was app Board of Trustees and ordinating Committee gery, American Soc Cardiology, Heart Fa for Cardiovascular A geons approved the d The American Associat as follows: Gersh BJ Naidu SS, Nishimura Bernard J Gersh, MB, ChB, DPhil, FACC, FAHA, Co-Chair* Barry J Maron, MD, FACC, CoChair* Robert O Bonow, MD, MACC, FAHA, Joseph A Dearani, MD, FACC,§,k Michael A Fifer, MD, FACC, FAHA,* Mark S Link, MD, FACC, FHRS,* Srihari S Naidu, MD, FACC, FSCAI,* Rick A Nishimura, MD, FACC, FAHA, Steve R Ommen, MD, FACC, FAHA, Harry Rakowski, MD, FACC, FASE,** Christine E Seidman, MD, FAHA, Jeffrey A Towbin, MD, FACC, FAHA, James E Udelson, MD, FACC, FASNC, and Clyde W Yancy, MD, FACC, FAHAkk

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2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.

2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons

2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy

This article reviews the information available to assist pharmacokineticists in the prediction of metabolic drug interactions. Significant advances in this area have been made in the last decade, permitting the identification in early drug development of dominant cytochrome P450 (CYP) isoform(s) metabolising a particular drug as well as the ability of a drug to inhibit a specific CYP isoform. The major isoforms involved in human drug metabolism are CYP3A, CYP2D6, CYP2C, CYP1A2 and CYP2E1. Often patients are taking multiple concurrent medications, and thus an assessment of potential drug-drug interactions is imperative. A database containing information about the clearance routes for over 300 drugs from multiple therapeutic classes, including analgesics, anti-infectives, psychotropics, anticonvulsants, cancer chemotherapeutics, gastrointestinal agents, cardiovascular agents and others, was constructed to assist in the semiquantitative prediction of the magnitude of potential interactions with drugs under development. With knowledge of the in vitro inhibition constant of a drug (Ki) for a particular CYP isoform, it is theoretically possible to assess the likelihood of interactions for a drug cleared through CYP-mediated metabolism. For many agents, the CYP isoform involved in metabolism has not been identified and there is substantial uncertainty given the current knowledge base. The mathematical concepts for prediction based on competitive enzyme inhibition are reviewed in this article. These relationships become more complex if the inhibition is of a mixed competitive/noncompetitive nature. Sources of uncertainty and inaccuracy in predicting the magnitude of in vivo inhibition includes the nature and design of in vitro experiments to determine Ki, inhibitor concentration in the hepatic cytosol compared with that in plasma, prehepatic metabolism, presence of active metabolites and enzyme induction. The accurate prospective prediction of drug interactions requires rigorous attention to the details of the in vitro results, and detailed information about the pharmacokinetics and metabolism of the inhibitor and inhibited drug. With the discussion of principles and accompanying tabulation of literature data concerning the clearance of various drugs, a framework for reasonable semiquantitative predictions is offered in this article.

Use of In Vitro and In Vivo Data to Estimate the Likelihood of Metabolic Pharmacokinetic Interactions

2011;58;2703-2738; originally published online Nov 8, 2011; J. Am. Coll. Cardiol. W. Yancy Rakowski, Christine E. Seidman, Jeffrey A. Towbin, James E. Udelson, and Clyde Fifer, Mark S. Link, Srihari S. Naidu, Rick A. Nishimura, Steve R. Ommen, Harry Bernard J. Gersh, Barry J. Maron, Robert O. Bonow, Joseph A. Dearani, Michael A. Thoracic Surgeons Society for Cardiovascular Angiography and Interventions, and Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, of Thoracic Surgery, American Society of Echocardiography, American Society Developed in Collaboration With the American Association for Guidelines Cardiology Foundation/American Heart Association Task Force on Practice Cardiomyopathy: Executive Summary: A Report of the American College of 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic This information is current as of May 14, 2012 http://content.onlinejacc.org/cgi/content/full/58/25/2703 located on the World Wide Web at: The online version of this article, along with updated information and services, is

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2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Executive Summary

The interactions between digoxin and quinine and quinidine that affect the renal and biliary clearances of digoxin were investigated in eight healthy subjects. Digoxin (0.5 to 0.75 mg/day) was given alone and with concomitant administration of quinine (750 mg/day) to reach a steady-state level. In four of the subjects, the study was repeated by administration of equimolar doses of the diastereoisomer quinidine together with digoxin, enabling a within-subject comparison of the effects of the two isomers on digoxin clearance. The biliary excretion of digoxin was studied by use of a modified duodenal marker perfusion technique. A marked reduction was found in the steady-state biliary clearance of digoxin from control value 134 ± 57 ml/min (mean ± SD) to 87 ± 39 ml/min during treatment with quinine (p < 0.05) and from 95 ± 24 to 55 ± 27 ml/min during treatment with quinidine (p < 0.01; n = 4). Quinidine reduced the renal clearance of digoxin (155 ± 26 versus 110 ± 21 ml/min) (p < 0.05; n = 4), whereas quinine had no such effect (177 ± 40 versus 185 ± 53 ml/min; not significant). These findings explain the difference in magnitude between quinidine and quinine in regard to the interaction with digoxin and imply a different degree of stereoselectivity for these isomers in the renal and biliary secretory systems of digoxin.

Clinical Pharmacology and Therapeutics (1990) 47, 20–26; doi:10.1038/clpt.1990.3

Interactions in the renal and biliary elimination of digoxin: stereoselective difference between quinine and quinidine.

Urinary excretion of desipramine (DMI) and 2-hydroxydesipramine (2-OH-DMI) after single oral doses of 25 mg DMI was investigated in seven rapid and three slow debrisoquin hydroxylators, before and after pretreatment with either quinidine or its diastereoisomer quinine. After treatment with 800 mg quinidine daily for 2 days, excretion of 2-OH-DMI decreased by 96% in rapid hydroxylators and 68% in slow hydroxylators. After treatment with 750 mg quinine/day for 2 days, excretion of 2-OH-DMI in rapid hydroxylators was 54% lower than during the control experiment, whereas in slow hydroxylators no significant changes in the excretion pattern were observed. Unchanged DMI constituted only a minor fraction of recovered drug and no significant changes in its recovery were observed in either phenotypic group after pretreatment with quinidine or quinine. Thus both quinidine and quinine decreased the excretion of 2-OH-DMI. At similar does the effect of quinidine was much stronger than that of quinine, virtually transforming rapid hydroxylators into slow hydroxylators. The mechanism probably involves a stereoselective inhibition of DMI 2-hydroxylation.

Inhibition of desipramine 2-hydroxylation by quinidine and quinine.

The interaction between digoxin and verapamil was studied in six patients (mean age +/- SD, 61 +/- 5 years) with chronic atrial fibrillation. The effects of adding verapamil (240 mg/day) on steady-state plasma concentrations and renal and biliary clearances of digoxin were studied in a crossover manner. The biliary clearance of digoxin was determined by a duodenal perfusion technique. Verapamil induced a 44% increase in steady-state plasma concentrations of digoxin, from 0.80 +/- 0.24 to 1.15 +/- 0.40 nmol/L (p less than 0.01). The biliary clearance of digoxin decreased by 43%, from 187 +/- 89 to 101 +/- 55 ml/min (p less than 0.05), in the presence of verapamil, whereas the renal clearance was unaffected (153 +/- 31 versus 173 +/- 51 ml/min; difference not significant). Our results indicate that the main inhibitory effect of verapamil on digoxin elimination is on the biliary route.

Digoxin-verapamil interaction: reduction of biliary but not renal digoxin clearance in humans.

Quinidine is known to reduce the renal clearance of digoxin, but this effect does not completely explain the influence of quinidine on the total clearance of digoxin. We therefore studied the effect of quinidine administration on biliary clearance of digoxin in five patients with atrial fibrillation. Biliary clearance of digoxin under steady state conditions before and during treatment with quinidine was investigated using a duodenal-marker-perfusion technique. Quinidine caused an average 42% (range 21-65%, P less than 0.02) reduction of the measured biliary clearance of digoxin. We conclude that the biliary effect adds to the previously demonstrated inhibitory effect of quinidine on the renal clearance of digoxin and helps to explain the decrease in total clearance of the drug. This is the first demonstration in man of a pharmacokinetic drug interaction at the level of biliary excretion.

Quinidine reduces biliary clearance of digoxin in man.

The total plasma and partial metabolic and renal clearances of theobromine and theophylline were determined in 13 healthy volunteers. Total plasma clearance for theobromine was 46% greater than that for theophylline, but the unbound clearances were almost identical. Theobromine renal clearance was 67% greater than that for theophylline but most of the difference was due to the lower protein binding of theobromine (free fraction = 0.86 compared to 0.58 for theophylline). Clearance by N-demethylation at the 3-position was 3.7-fold higher (unbound clearance 2.5-fold higher) for theobromine than for theophylline, showing that the position of the other methyl substituent (positions 1 or 7) is a major determinant of metabolic rate. There was a high degree of correlation between theophylline and theobromine plasma clearances (r = 0.86) and also between partial metabolic clearances both within drugs and across drugs (r = 0.65-0.99). The renal clearances of theophylline and theobromine were also correlated (r = 0.71). The results support the view that theophylline and theobromine are metabolized by a common group of cytochromes P-450 under similar regulatory control. Theobromine is a good model compound for assessing the activity of these enzymes in man as it has low pharmacological activity and low protein binding, its total and partial metabolic clearances correlate closely with those of theophylline, and close to 100% of the dose can be recovered as known metabolites.

R. Dahlqvist

Papers

Interactions in the renal and biliary elimination of digoxin: stereoselective difference between quinine and quinidine.

Inhibition of desipramine 2-hydroxylation by quinidine and quinine.

Digoxin-verapamil interaction: reduction of biliary but not renal digoxin clearance in humans.

Quinidine reduces biliary clearance of digoxin in man.

Comparison of theophylline and theobromine metabolism in man.