Tubular Secretion Of Digoxin Research Articles

Verapamil metabolites: potential P-glycoprotein-mediated multidrug resistance reversal agents.

Multidrug resistance in cancer chemotherapy frequently correlates with overexpression of the P-glycoprotein drug transporter. Attempts to reverse P-glycoprotein-mediated multidrug resistance with racemic verapamil or its less toxic (R)-enantiomer have been complicated by cardiotoxicity. The objective of this study was to investigate the effects of the major verapamil metabolite, norverapamil, as well as the PR-22 and D-620 metabolites, on P-glycoprotein-mediated drug transport. We measured the basolateral-to-apical fluxes of the P-glycoprotein substrates digoxin and vinblastine in the presence and absence of verapamil, (R)-norverapamil, (S)-norverapamil, racemic norverapamil, PR-22, or D-620 across confluent monolayers of Madin-Darby canine kidney (MDCK) cells that express P-glycoprotein on their apical membranes. Verapamil and norverapamil nonstereospecifically inhibited the renal tubular secretion of digoxin and vinblastine similarly in a dose-dependent manner. However, there was no decrease in the cellular accumulation of digoxin and vinblastine, suggesting that neither verapamil nor norverapamil prevent the substrates from entering the MDCK cells. Furthermore, the norverapamil metabolite P-22 also inhibited the secretion of these P-glycoprotein substrates. Our results suggest that the verapamil metabolites norverapamil and PR-22, which are less cardiotoxic than the parent compound, have comparable inhibitory abilities to verapamil (norverapamil greater than PR-22) and may be useful in reversing resistance to P-glycoprotein substrates.

A model for the prediction of digoxin-drug interactions at the renal tubular cell level.

Digoxin-drug interactions are relatively common causes of digitalis toxicity. Recently, the clinical importance of the renal tubular secretion of digoxin has been proven by documenting drug interactions at this level. The authors describe a model using cultured renal tubular cell monolayers that can be used to predict drug interactions with the cardiac glycoside. This model accurately documents known clinical digoxin interactions such as those with verapamil and propafenone. The common feature of these interactions is that they involve P-glycoprotein substrates (e.g., digoxin, vincristine, vinblastine) or inhibitors (e.g., quinidine, cyclosporine). In the case of the newly described interaction of digoxin with itraconazole, the model preceded the emergence of clinical cases.

Pubertal changes in net renal tubular secretion of digoxin.

To evaluate the effect of puberty on the net renal tubular secretion of digoxin, we measured the ratio of digoxin clearance to creatinine clearance in 23 patients aged 4 to 21 yr and correlated this ratio with both sexual maturity (Tanner stage) and chronologic age. All subjects were at steady-state levels for digoxin treatment; all had normal serum creatinine values for age as well as normal serum potassium levels. Mean ratio for immature children (n = 14, Tanner 1 through 3.5) was 1.45 +/- 0.66. Mean ratio for mature adolescents (n = 9, Tanner 4 through 5) was 0.95 +/- 0.28. The difference between the two groups was significant (P less than 0.05). When patients were regrouped by age using either 13 or 15 yr as a cutoff, the difference in ratios was no longer statistically significant. Based on 45 subjects (new and from our previous study) aged 2 mo to 80 yr, there was a significant decrease in the clearance ratio with increasing age, but when the 23 subjects aged 4 to 21 yr were analyzed separately, the correlation between ratio and age was not significant. It appears that the decrease in net renal tubular secretion of digoxin from childhood to adulthood correlates better with full sexual maturation at puberty (Tanner 4 through 5) than with chronologic age. This observation may represent a developmental change in pharmacokinetics with broader significance than for digoxin disposition alone.

Interactions between digoxin and potassium-sparing diuretics.

A kinetic and hemodynamic study of digoxin was performed in six healthy subjects and similar studies were performed during digoxin with spironolactone and with triamterene. Spironolactone reduced renal tubular secretion of digoxin and attenuated its positive inotropic effect (evaluated by systolic time intervals and echocardiography) and triamterene reduced the extrarenal elimination of digoxin, but induced no changes in digoxin-elicited inotrophy. It is suggested that the renal handling of digoxin is influenced by the intracellular potassium concentration in the renal tubular cell. The results indicate a drug-receptor interaction between spironolactone metabolites and digoxin at the hypothetical inotropic digitalis receptor. Amiloride has been reported to suppress digoxin inotropism, whereas spironolactone induces minor inhibition and triamterene does not affect digoxin inotropism.

Renal digoxin clearance: dependence on plasma digoxin and diuresis.

The renal handling of digoxin in animals involves glomerular filtration, tubular secretion and tubular reabsorption, while only glomerular filtration and tubular secretion have been described in humans. The influence of plasma digoxin and urine flow on the renal handling of digoxin was investigated in 6 healthy volunteers. Non-glomerular renal excretion of digoxin (tubular secretion minus tubular reabsorption) was inversely correlated with plasma digoxin concentration and directly with urine flow. Hence, the present study demonstrated the occurrence of tubular reabsorption in addition to glomerular filtration and tubular secretion of digoxin. The results suggest that renal clearance of digoxin should be increased by increased urine flow, which might be of importance during digoxin toxicity.

Acute vasodilator therapy increases renal clearance of digoxin in patients with congestive heart failure.

We studied the effect of vasodilator therapy on renal digoxin clearance in patients with chronic congestive heart failure. Intravenous administration of nitroprusside or hydralazine to eight patients with severe heart failure produced the expected increase in cardiac output and a decrease in central circulatory pressure. Renal clearance of sodium para-aminohippurate and estimated renal blood flow increased without a change in glomerular filtration rate. Total renal clearance of digoxin increased by 50% during vasodilator therapy. Thus, acute administration of vasodilator increases renal digoxin clearance without changing glomerular filtration rate, suggesting an increase in tubular secretion of digoxin. Long-term vasodilator therapy may alter the maintenance dosage of digoxin required for optimal treatment of patients in congestive heart failure.

Amiloride-induced changes in digoxin dynamics and kinetics: abolition of digoxin-induced inotropism with amiloride.

Digoxin dynamics and kinetics were studied in six healthy subjects with and without amiloride. Amiloride increased mean renal digoxin clearance from 1.3 to 2.4 ml . kg-1 . min-1 (p less than 0.001) due to increased tubular secretion of digoxin, while the glomerular filtration rate was unchanged. This might be caused by an increase in intracellular potassium concentration in the tubular cells provoked by amiloride. In contrast, the extrarenal clearance of digoxin was almost blocked by amiloride; it fell from a mean of 2.1 to 0.2 ml . kg-1 . min-1 (p less than 0.025). Total body clearance tended to fall, but the decrease was not statistically significant. EValuation of myocardial contractility by systolic time intervals revealed a concentration-response relationship between digoxin and changes in preejection period index when digoxin was given alone (rs = 0.750, p less than 0.001). Pretreatment with amiloride abolished this relationship (rs = 0.307, p = NS). Blood pressure and echocardiographically determined left ventricular end-diastolic diameter measurements indicated no changes in the left ventricular post- and preload. It is concluded that amiloride suppressed digoxin-induced inotropism.

The effect of quinidine on digoxin kinetics in cardiac patients.

The pharmacokinetics of digoxin was studied in 11 subjects before and during quinidine treatment. Renal clearances of digoxin and creatinine were calculated from plasma concentrations and urinary excretions of digoxin and creatinine in subjects on long-term digoxin treatment. The investigations were repeated in the same subjects during administration of quinidine. Renal clearance of digoxin decreased, while plasma concentration of digoxin and renal excretion of digoxin increased in the presence of quididine, indicating substantial changes of digoxin kinetics, induced by quinidine. The reduction in renal clearance of digoxin may be due to a specific inhibition of tubular secretion of digoxin. The considerable rise of the plasma digoxin level and the increased excretion of digoxin support the assumption of a major extrarenal mechanism of interaction.