Malabsorption as a complication of congestive heart failure

Berkowitz, Donald; Groll, Millard N.; Likoff, William

doi:10.1016/0002-9149(63)90029-8

Cited by 59 publications

(24 citation statements)

References 6 publications

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“…Predicting Stereoselective PK of Carvedilol-A PBPK Approach 1111 at ASPET Journals on May 11, 2018 dmd.aspetjournals.org CHF (Berkowitz et al, 1963;Sica, 2003). Moreover, in CHF, the absorption of drugs with low solubility is more susceptible to changes in intestinal blood flow; therefore, for drugs like carvedilol (BCS class II)…”

Section: Discussionmentioning

confidence: 99%

“…In CHF, the reduced blood flows to the gastrointestinal tract, the peripheral tissues, as well as the liver and the kidneys can affect the drug absorption, distribution, metabolism, and elimination (ADME) (Berkowitz et al, 1963;Zelis et al, 1975;Sica, 2003;Ogawa et al, 2013). These reductions in the organ blood flows are associated with the severity of disease (Leithe et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

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Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach

Rasool

Khalil

Läer

2016

Drug Metabolism and Disposition

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Chronic heart failure (CHF) is a systemic low perfusion syndrome resulting from impairment in the pumping function of the heart. The decrease in blood supply to body organs can potentially affect the pharmacokinetics (PK) of the drugs being administered. Carvedilol is administered as a racemic mixture and undergoes extensive stereoselective first pass metabolism. For such a drug, the pathophysiological changes occurring in CHF can have a profound impact on PK, and thus the resulting pharmacodynamic response, of both enantiomers. The aim of the current work was to predict stereoselective disposition of carvedilol after incorporating the pathophysiological changes in CHF into a whole-body physiologically based PK model using Simcyp, and to scale that model to pediatric CHF patients on a physiologic basis to investigate whether the same changes in the adult model can also be adopted for children. The developed model has successfully described PK of carvedilol enantiomers in healthy adults and in patients after the incorporation of reduced organ blood flows, as seen by the visual predictive checks and the calculated observed/predicted ratios for all PK parameters of interest. In contrast to adults, pediatric patients up to 12 years of age were better described without the reductions in organ blood flow, whereas older pediatric patients were better described after incorporating organ blood flow reductions. These findings indicate that the incorporated blood flow reductions in the adult model cannot be directly adopted in pediatrics, at least for the young ones; however, to draw definite conclusions, more data are still needed.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach

Rasool

Khalil

Läer

2016

Drug Metabolism and Disposition

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“…The term 1 K· FD represents the diffusion resistance of the epithelium and depends on permeability and area of the absorbing surface. Although experimental data are lacking, pathological changes of the intestinal epithelium in patients with cardiac failure, primarily oedema, have been used to explain decreased absorption in such patients (Berkowitz et al 1963 has been described in the cat (Svanvik, 1973), whose mucosal anatomy resembles that of man. The quantity of drug (R) represents the drug that recirculates or is 'trapped' in the villus.…”

Section: Pathophysiology Of Cardiac Failurementioning

confidence: 99%

Pharmacokinetics in Patients with Cardiac Failure

Benowitz

Meister

1976

Clinical Pharmacokinetics

131

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Cardiac failure is often associated with disturbances in cardiac output, autonomic nervous system activity, central and systemic venous pressures, and sodium and water metabolism. These disturbances influence the extent and pattern of tissue perfusion, may lead to tissue hypoxia and visceral congestion, and may alter gastrointestinal motility. By these mechanisms, cardiac failure potentially affects absorption and disposition characteristics of drugs, which may necessitate adjustment in dosage regimen for optimum therapy. Lignocaine is the drug which has been studied most extensively in cardiac failure. Volumes of distribution and clearance are decreased. As a drug whose metabolism is largely limited by liver blood flow, decreased blood flow to the liver accounts for some of the change in clearance, but impaired hepatic metabolism appears also to play a role in some patients. Accumulation of active metabolites of lignocaine and procainamide in patients with cardiac failure can influence therapeutic and toxic effects. Theophylline metabolism, which is largely independent of blood flow, appears to be reduced significantly in patients with severe cardiac failure and necessitates reduction of dosage. In the presence of severe cardiac failure, digoxin clearance may be less than anticipated on the basis of estimates of renal function. Quinidine plasma levels may be higher after single doses due to reduced volume of distribution. Quinidine metabolites are believed not to be pharmacologically active but may create confusion with nonspecific assays. Specific assays are recommended in cardiac failure, especially complicated by renal insufficiency. Data are lacking relating pharmacokinetic alterations to haemodynamic measurements in patients with cardiac failure. Whereas the direction of change in pharmacokinetic parameters may be predicted, variability in the magnitude of change is so great that determination of drug concentration in blood remains as essential adjunct to therapy.

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“…Other factors possibly leading to an altered rate or extent of drug absorption in cardiac failure include intestinal wall edema, delayed gastric emptying, decreased intestinal motili ty, changes in gastrointestinal pH, secretions and gut flora, and the possibility of drug-drug interactions [ 1,18,19], Our results, however, indicate that left-ventricular cardiac failure has no influence upon the absorption of drug from digoxin tablets. We estimated the extent of availability by two independent methods using plasma and urine concentrations, re spectively.…”

Section: Discussionmentioning

confidence: 75%

Unchanged Absorption of Digoxin Tablets in Patients with Cardiac Failure

Meister¹,

Benowitz²,

Benet³

1984

Pharmacology

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In 6 patients with severe left-sided cardiac failure the absorption of drug from digoxin tablets was assessed by simultaneous administration of a commercially available tablet and of an intravenous tracer dose before and during therapy. Lag time, peak time, and dose-normalized increase in plasma concentration did not change in spite of clinical improvement. Two independent measures of the extent of availability, based on plasma and urine measurements, also remained unchanged and their average was similar to that reported for normals. There was, however, a great interindividual variability in absorption. We conclude that the absorption of digoxin tablets is unchanged in patients with left-sided cardiac failure.

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Malabsorption as a complication of congestive heart failure

Cited by 59 publications

References 6 publications

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach

Pharmacokinetics in Patients with Cardiac Failure

Unchanged Absorption of Digoxin Tablets in Patients with Cardiac Failure

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