Kristin M. Williamson

Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers

Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater antihypertensive activity than the parent compound. Coadministered drugs that inhibit or induce metabolic processes may therefore alter the pharmacokinetics and pharmacologic response of losartan and E3174.

The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers.

Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady‐state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open‐label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that flvastatin did not significantly change the steady‐state AUC0–24 or half‐life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require both CYP2C9 and CYP3A4 inhibition.

Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients

The objective of this study was to examine the pharmacokinetic and pharmacodynamic consequences of concomitant administration of fluoxetine and carvedilol in heart failure patients. Fluoxetine (20 mg) or matching placebo was administered in a randomized, double‐blind, two‐period crossover study to 10 patients previously identified as extensive metabolizers of CYP2D6 substrates. Patients were maintained on a carvedilol dose of 25 or 50 mg bid and given fluoxetine/placebo for a minimum of 28 days. Plasma was collected over the 12‐hour carvedilol dosing interval, and the concentrations of the R(+) and S(−) enantiomers of carvedilol were measured. CYP2D6 phenotype was assessed during each study period using dextromethorphan (30 mg). Changes in autonomic modulation between study periods were measured by heart rate variability in the time and frequency domains using ambulatory electrocardiographic monitoring. Compared to placebo, fluoxetine coadministration resulted in a 77% increase in mean (± SD) R(+) enantiomer AUC0–12 (522 ± 413 vs. 927 ± 506 ng•h/mL, p = 0.01) and a nonsignificant increase in S(−) enantiomer AUC (244 ± 185 vs. 330 ±179 ng•h/mL, p = 0.17). Mean apparent oral clearance for both enantiomers decreased significantly with fluoxetine administration (R(+): 10.3 ± 7.2 vs. 4.5 ± 2.2 mL/min/kg; S(−): 22.5 ± 12.3 vs. 12.6 ± 7.4 mL/min/kg; p = 0.004 and 0.03, respectively). No differences in adverse effects, blood pressure, or heart rate were noted between treatment groups, and there were no consistent changes in heart rate variability parameters. In conclusion, fluoxetine administration resulted in a stereospecific inhibition of carvedilol metabolism, with the R(+) enantiomer increasing to a greater extent than the S(−) enantiomer. However, this interaction was of little clinical significance in our sample population.

Pharmacogenetics and Heart Failure: A Convergence with Carvedilol

The introduction of a new cardiovascular drug provides the opportunity to reevaluate traditional dosing practices that are often population based and not patient specific. Understanding the pharmacokinetics of a new drug helps guide therapy, but variability in patient response may still occur, particularly in patients with altered physiology. This becomes more challenging when drugs demonstrate highly variable clearances, are administered as isomers, or are metabolized by genetically regulated enzymes. Carvedilol (Coreg; SmithKline Beecham Pharmaceuticals, Philadelphia, PA, and Boehringer Mannheim, Gaithersburg, MD), a nonselective @-blocker that vasodilates through a1-blockade, is the first P-blocker approved for use in heart failure. We present a brief review of the clinical pharmacology of carvedilol, highlighting the role of CYP2D6 metabolism, and emphasize the strategy for dosage initiation and patient monitoring in the patient with heart failure. Over the past decade, there has been a heightened appreciation for the role of cytochrome P-450 isoenzymes in drug metabolism. The activities of CYP2D6, CYP2C19, and CYP2C9 are under genetic control.’ Individuals classified as extensive metabolizers (EMS) are fully capable of activating or deactivating substrates of the respective

Is There an Expanded Role for Digoxin in Patients with Heart Failure and Sinus Rhythm? A Protagonist Viewpoint

The evidence supporting the efficacy of digoxin in patients with heart failure who are in sinus rhythm is substantial. Digoxin improves hemodynamics, exercise capacity, symptoms, and quality of life and reduces hospitalizations. All of this is accomplished with a drug that is very inexpensive and can be given once daily. Its safety has been established through the DIG trial. Although digoxin does not decrease mortality beyond that of diuretics and ACE inhibitors, it does not increase mortality, unlike many positive inotropes. Furthermore, digoxin, in addition to ACE inhibitors and a diuretic, decreases the hospitalization rate due to worsening of heart failure. From a managed care perspective, as well as that of the patient, this is of enormous benefit. A pharmacoeconomic analysis estimated that continuation of digoxin in patients with stable congestive heart failure could save the healthcare system an estimated

Effect of fluoxetine on carvedilol stereo‐specific pharmacokinetics in patients with heart failure

400 million, based on costs from one hospital. The issue is not whether to use digoxin in these patients, but rather, how early to initiate therapy. From some of the recent data in patients with systolic dysfunction and mild heart failure, as well as knowledge of the neurohormonal activation that occurs early in these patients, it could be suggested that early use of neurohormonal modulators, including digoxin, would decrease the progression of heart failure. Thus, rather than waiting for symptoms despite optimal doses of an ACE inhibitor and diuretic, as suggested by the AHCPR practice guideline for heart failure, initiation of digoxin therapy in patients as early as NYHA class II at a dosage that will achieve a serum concentration of 1.0 ng/mL or less should occur. With the understanding of digoxins effect on the neurohormonal systems, its role in patients with preserved systolic function needs to be reexplored. The debate can now focus on asymptomatic patients or those with preserved systolic function. Could these patients benefit from therapy with digoxin as well?

Is There a Role for Digoxin in Patients With Systolic Dysfunction

Clinical Pharmacology & Therapeutics (1999) 65, 148–148; doi:

Digoxin toxicity : An evaluation in current clinical practice

In early placebo‐controlled trials in patients with heart failure who were in sinus rhythm, digoxin improved hemodynamics, signs and symptoms of heart failure, and exercise capacity, and decreased functional deterioration and the need for pharmacologic cointervention. A more recent trial showed that withdrawing digoxin from patients who were clinically stable while receiving diuretics and angiotensin‐converting enzyme (ACE) inhibitors often resulted in clinical deterioration, whereas continuing the agent maintained stability. Which patients should initially be treated with digoxin remains to be determined. The effects of digoxin on mortality in patients who are receiving ACE inhibitors must also be established.