Quinidine reduces biliary clearance of digoxin in man

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.     

The effects of mannitol diuresis on digoxin and phenobarbital handling by the kidney: implications for tubular reabsorption and secretion of the cardiac glycoside

The effect of mannitol diuresis on the renal clearance of digoxin and phenobarbital was studied in dogs. Mannitol diuresis significantly increased the clearance of digoxin and the ratio digoxin: inulin clearances (from 0.7 +/- 0.2 to 1.1 +/- 0.25). The increase in phenobarbital: inulin clearance ratio was significantly higher than the increase in the digoxin: inulin clearance ratio (4.9 fold vs 1.66 fold) (p less than 0.005). Mannitol diuresis did not significantly affect inulin clearance, nor digoxin protein binding during the experimental period while there was a significant increase in PAH clearance. Significant correlations were found between urine flow rate and digoxin renal clearance or digoxin: inulin clearance ratio. The increase in the ratio drug: inulin clearance with diuresis correlated inversely with the initial ratio; animals with more predominant net reabsorption had a higher increase in ratio. These studies suggest that the mannitol-induced increase in digoxin clearance stems from a combination of increased renal blood flow enhancing digoxin secretion, and increased urine flow rate inhibiting its reabsorption. We conclude that urine flow rate and renal blood flow are important determinants of the renal clearance of digoxin, independent of GFR. Any study assessing the effect of pathophysiological states or drug interactions on digoxin renal clearance must control for these factors.     

Renal function and digoxin clearance during quinidine therapy

Summary. To investigate further the handling of digoxin by the kidneys during quinidine therapy, clearances of digoxin, ⁵¹Cr-EDEA, PAH and endogenous creatinine were measured together with β₂-microglobulin in the urine before and during quinidine therapy in 10 patients on maintenance digoxin therapy. Renal clearance of digoxin (corrected for 30% plasma binding) decreased on the average by 55% (137 ± 73 to 73 ± 25 ml/min, mean ± SD). The steady state plasma concentration of digoxin increased more than twofold (1·0 ± 0·34 to 2·5 ± 0±79 nmol/l, mean ± SD). The clearances of ⁵¹Cr-EDTA and PAH were not altered during quinidine therapy, indicating that neither glomerular filtration nor total renal blood flow changed when quinidine was added. The ratio of the renal clearance of unbound digoxin to that of the glomerular filtration rate was above one for all 10 patients before quinidine, indicating the involvement of tubular secretion in the renal elimination of digoxin. After the administration of quinidine this ratio decreased in all patients (from 1·51 ± 0·30 to 0·83 ± 0·38, mean ± SD). Some patients had ratios well below one suggesting re-absorption of digoxin. β²-microglobulin excretion was unchanged during treatment with quinidine. It is concluded that a significant portion of the renal elimination of digoxin in man results from tubular secretion and that this excretory mechanism is inhibited by quinidine.     

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

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 less than 0.05) and from 95 +/- 24 to 55 +/- 27 ml/min during treatment with quinidine (p less than 0.01; n = 4). Quinidine reduced the renal clearance of digoxin (155 +/- 26 versus 110 +/- 21 ml/min) (p less than 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.     

Effects of quinidine on pharmacokinetics and pharmacodynamics of digitoxin achieving steady-state conditions

Quinidine has been reported to increase digoxin plasma concentrations, which increases the risk of digoxin overdose. The effect of quinidine on digitoxin pharmacokinetics is still controversial because most studies were not performed with subjects achieving definite steady-state conditions. To determine whether quinidine affects digitoxin kinetics and cardiac efficacy, we measured glycoside plasma concentrations and renal excretion as well as ECG parameters and systolic time intervals before and during quinidine dosing in eight healthy subjects at steady state. Mean (+/- SD) digitoxin plasma concentrations and renal excretion increased from 13.6 +/- 2.2 ng/ml and 16.1 +/- 5.8 micrograms/24 hours before dosing to 19.7 +/- 3.1 ng/ml and 23.4 +/- 4.9 micrograms/24 hours, respectively, during quinidine dosing for 32 days. While renal digitoxin clearance was not noticeably changed by quinidine, total digitoxin clearance and extrarenal digitoxin clearance decreased by an average of 32% and 40.5%, respectively. The elimination t1/2 was prolonged from 150.3 +/- 20.6 to 202.6 +/- 37.5 hours. The increased digitoxin plasma level is pharmacodynamically active. We conclude that there is a clinically important interaction between digitoxin and quinidine, but it is to a lesser extent and is caused by different mechanism, in part, than the interaction between digoxin and quinidine.     

Lack of pharmacodynamic interactions between quinidine and digoxin in isolated atrial muscle of guinea pig heart

Quinidine has been reported to have no effect on the positive inotropic action of digoxin observed in isolated cardiac muscle preparations. This is surprising because quinidine has been shown to reduce Na+ influx in cardiac muscle. The conditions which increase Na+ influx stimulate the glycoside binding to Na+- and K+-activated Mg++-dependent ATP phosphohydrolase (Na+,K+-ATPase), and therefore quinidine may be expected to have an opposite effect. Thus, the effects of quinidine on cardiac muscle and its possible interactions with digoxin were re-evaluated using electrically paced left atrial muscle preparations of guinea pig heart. Quinidine caused a frequency- and concentration-dependent decrease in maximal upstroke velocity and amplitude of the action potential without altering resting membrane potential. In addition, quinidine prolonged action potential duration markedly in a frequency-dependent manner. Despite action potential prolongation, the alkaloid reduced net Na+ influx as determined by a decrease in steady-state ouabain-sensitive 86Rb+ uptake. Under these conditions, however, quinidine failed to reduce the rate of onset or the maximal positive inotropic effect of digoxin; or did it reduce digoxin binding to Na+,K+- ATPase in beating atrial muscle preparations. Benzocaine, which reduced net Na+ influx without increasing the action potential duration, also failed to affect the peak inotropic effect of digoxin or the glycoside binding. Quinidine had no direct effects on glycoside binding to isolated cardiac Na+,K+-ATPase. Moreover, [3H]ouabain binding to isolated enzyme was relatively insensitive to changes in Na+ concentrations between 1 and 8 mM although binding was stimulated clearly by Na+ above 8 mM. These results indicate that quinidine, at therapeutic concentrations, does not interact pharmacodynamically with digoxin in isolated cardiac muscle.     

Digoxin disposition kinetics in dogs before and during azotemia

The purpose of this study was to evaluate the disposition kinetics of digoxin after the administration of a single intravenous dose to the same dogs before and during azotemia. The digoxin plasma concentration-time data were fitted to a multicompartment model using nonlinear regression analysis. During azotemia, the biological half-life of digoxin was prolonged in six of seven dogs, while digoxin renal clearance, body clearance and apparent volume of distribution were significantly decreased. There was a corresponding increase in the apparent volume of the "central" compartment of digoxin. Approximately 45% of a digoxin dose was excreted by the kidney in these animals indicating a substantial nonrenal component to digoxin elimination in the dog. This nonrenal elimination did not change during azotemia, despite a decrease in renal clearance by 61%.     

Substantial pharmacokinetic interaction between digoxin and ritonavir in healthy volunteers

BACKGROUND: Ritonavir is a potent in vitro inhibitor of several cytochrome P450 isozymes and ABC transporters including the efflux pump P-glycoprotein (P-gp). This study assessed the effect of repetitive ritonavir administration on digoxin distribution and total and renal digoxin clearance as a marker for P-gp activity in vivo. METHODS: In a randomized, placebo-controlled crossover study, 12 healthy male participants received oral ritonavir (300 mg twice daily) for 11 days. With the assumption that ritonavir steady state had been reached, 0.5 mg digoxin was given intravenously on day 3. Digoxin concentrations were determined in plasma and urine by radioimmunoassay, and plasma ritonavir concentrations were determined by liquid chromatography-tandem mass spectrometry. Digoxin kinetics was estimated by compartmental and noncompartmental analyses, by use of the area under the plasma concentration-time curve, and the corresponding digoxin amount excreted into urine was used for digoxin clearance calculations. RESULTS: Ritonavir significantly (P <.01) increased digoxin area under the plasma concentration-time curve from time 0 to infinity by 86% and its volume of distribution by 77% and decreased nonrenal and renal digoxin clearance by 48% and 35%, respectively. Digoxin terminal half-life in plasma increased by 156% (P <.01). CONCLUSION: This inhibition of renal digoxin clearance is likely caused by ritonavir inhibition of P-gp. Its extent is considerable and similar to the effect of other potent P-gp inhibitors on digoxin disposition such as quinidine. These findings may, therefore, indicate that the pharmacokinetics of P-gp substrates sharing the renal tubular elimination pathway will be affected when combined with therapeutic doses of ritonavir in antiretroviral treatment regimens. In addition and contrarily to quinidine, these data indicate that ritonavir promotes digoxin distribution in the body.     

Drug interactions with calcium inhibitors in man

The most common interactions concern cardiovascular drugs. The combination of calcium antagonists (CA) and beta-blockers is more effective than single-agent therapy in stable effort angina and hypertension. But there is an increased risk of hemodynamic or electrophysiological side effects in patients with left ventricular or sinus dysfunction, or disturbances of conduction. Pharmacokinetic interactions have been observed in particular with verapamil (VE) which increases propranolol bioavailability. VE increases the T1/2 of elimination and plasma digoxin concentration following single or prolonged administration. The primary mechanism appears to be renal. These modifications increase the risk of digitalis intoxication. Diltiazem (DTZ) inconsistently increases steady state plasma digoxin levels. In healthy subjects, nifedipine (NF) increases plasma digoxin concentrations and decreases digoxin renal clearance. These findings have not been observed in patients with heart failure. NF therefore leads to less marked modifications in digitalis pharmacokinetics than do VE and DTZ. Nitrendipine and nicardipine interact only slightly with digoxin, and consequently there are no pharmacodynamic effects. In healthy subjects, VE increases quinidine t1/2 and markedly decreases its metabolic clearance. Conversely, quinidine increases plasma NF levels. The primary CA are extensively metabolized by liver microsome oxidases. These result in interactions with the drugs that are also metabolized by these enzymes, or able to modify their activity. VE and DTZ decrease antipyrine and carbamazepine clearance. VE, DTZ and nicardipine lead to a marked increase in plasma ciclosporin levels. Cimetidine, but not ranitidine, increases plasma NF levels. The effects on VE are controversial. Prolonged rifampicin treatment decreases plasma VE levels.     

Digoxin-quinidine-spironolactone interaction

Digoxin kinetics are substantially altered by quinidine and by spironolactone. We evaluated the effect of the combination of quinidine and spironolactone on digoxin kinetics and compared it to the effect on digoxin of each drug alone. Six normal subjects each received a 1.0-mg intravenous dose of digoxin alone, digoxin with quinidine, digoxin with spironolactone, and digoxin with both quinidine and spironolactone. Spironolactone and quinidine, alone and in combination, reduced digoxin systemic, renal, and nonrenal clearances and prolonged digoxin elimination t 1/2. A greater alteration in digoxin kinetics was induced by quinidine than by spironolactone, and an even greater effect resulted from the combination. We did not assess clinical consequences of the interaction. We advise reduction in digoxin dose, careful clinical evaluation, and measurement of serum digoxin concentrations when digoxin is used in combination with quinidine and spironolactone.     

Cimetidine transport in isolated brush border membrane vesicles from bovine choroid plexus

The purpose of this study was to elucidate the mechanisms involved in the transport of cimetidine across the brush border membrane of choroid plexus epithelium. Brush border membrane vesicles were prepared from bovine choroid plexus and the uptake of [3H]cimetidine was studied using the methods of rapid vacuum filtration and scintillation counting. Cimetidine accumulated in the vesicles with time reaching equilibrium within 2 hr. The amount of cimetidine taken up by the vesicles at equilibrium decreased with increasing extravesicular media osmolarity suggesting that cimetidine accumulates in an osmotically reactive intravesicular space. Binding of cimetidine to the membrane was estimated to be less than 18%. Michaelis-Menten studies demonstrated that cimetidine transport involved both a saturable and a nonsaturable component. The Vmax and Km (mean +/- S.E.) were 16.7 +/- 5.9 pmol/sec/mg protein and 58.1 +/- 3.1 microM, respectively, suggesting that cimetidine is transported across the choroid plexus brush border membrane with a lower affinity and a higher capacity than across the renal brush border membrane. The organic cation, quinidine (0.1 mM), and the amino acid, histidine (20 mM), both significantly reduced the initial, but not the equilibrium, uptake of cimetidine. However, high concentrations (5 mM) of more polar organic cations including tetraethylammonium, as well as of several organic anions including salicylate did not inhibit cimetidine transport. Studies with unlabeled cimetidine revealed a countertransport phenomenon. Attempts to drive the concentrative uptake of cimetidine with various ion gradients were unsuccessful. Of note was the fact that an outwardly directed proton gradient could significantly accelerate the uptake of cimetidine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increase in serum digoxin concentration produced by quinidine does not increase the potential for digoxin-induced ventricular arrhythmias in dogs

Chronic treatment of dogs with digoxin alone, quinidine alone and digoxin in combination with quinidine was initiated in dogs to assess changes in arrhythmogenic potential associated with the quinidine-induced increase in serum digoxin concentration observed during combined digoxin and quinidine treatment. The arrhythmogenic potential of digoxin was evaluated through the use of the acetylstrophanthidin (AcS) tolerance test. AcS was infused at a rate of 5 micrograms/kg/min until ventricular arrhythmias occurred during a drug-free period and during chronic treatment with digoxin, quinidine and digoxin plus quinidine. The dose of AcS required to initiate ventricular arrhythmias is inversely related to the arrhythmogenic potential of digoxin present at the time of AcS infusion. Administration of quinidine alone in two different dosage regimens produced serum quinidine concentrations of 5.99 +/- 1.18 and 2.99 +/- 0.43 micrograms/ml and significantly increased AcS tolerance, whereas digoxin alone, over a wide range of serum digoxin concentrations, significantly decreased AcS tolerance. This decrease in AcS tolerance was linearly related to the serum digoxin concentration. The addition of quinidine treatment to animals receiving digoxin resulted in a significant elevation in the steady-state serum digoxin concentration. However, the AcS tolerance determined during the elevated serum digoxin concentration induced by quinidine was greater than that determined during treatment with the same dose of digoxin alone. Thus, quinidine administration to animals receiving digoxin resulted in a significant increase in the steady-state serum digoxin concentration but did not increase the arrhythmogenic potential of digoxin over that observed during treatment with the same dose of digoxin alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Desoxyrhaponticin (3,5-dihydroxy-4'-methoxystilbene 3-O-beta-D-glucoside) inhibits glucose uptake in the intestine and kidney: In vitro and in vivo studies.

Rhubarb extracts have been reported to improve oral glucose tolerance in diabetic animals. In the present study we have investigated the antidiabetic actions of desoxyrhaponticin, a major stilbene in rhubarb, as a glucose uptake inhibitor. Desoxyrhaponticin was demonstrated to inhibit glucose uptake in rabbit intestinal membrane vesicles as well as in rat everted gut sleeves, with IC50 values of 148.3 and 30.9 microM, respectively. Kinetics studies revealed that desoxyrhaponticin is a competitive inhibitor of glucose uptake in both systems. Moreover, desoxyrhaponticin could reduce glucose uptake in the intestinal membrane vesicles of both normal and diabetic rats. In addition, glucose uptake in the renal membrane vesicles of both normal and diabetic rats was reduced by desoxyrhaponticin. Under the inhibition of desoxyrhaponticin, uptake of glucose in both the intestinal and renal membrane vesicles of the normal rats was no different from that of the diabetic rats. The IC50 values of the uptake inhibition in the renal membrane vesicles of normal and diabetic rats were 118.8 and 115.7 microM, respectively. In a type 2 diabetic animal model in which rats have been treated with streptozotocin at the neonatal stage, postprandial hyperglycemia was significantly suppressed by oral administration of this compound (300 mg/kg b.wt.). These results suggest that desoxyrhaponticin is an agent that is potentially effective in controlling postprandial hyperglycemia in diabetes. The in vivo antidiabetic action of this compound can be explained, in part at least, by inhibition of glucose transport in the small intestine and inhibition of glucose reabsorption in the kidney.     

Effect of nifedipine on serum digoxin concentration and renal digoxin clearance

Nifedipine has been reported either to decrease or not to affect digoxin elimination. We studied the effect of oral nifedipine on steady-state digoxin concentrations and renal clearance in 20 healthy male subjects. After 2 wk of digitalization, all received digoxin, 0.375 mg a day, with placebo for 2 wk, then digoxin and nifedipine, 18.5 +/- 4 mg every 8 hr, for 2 wk, and then digoxin with placebo for 2 wk. Mean (+/- SD) digoxin concentrations of 0.74 +/- 0.20 and 0.75 +/- 0.25 ng/ml on placebo were not altered by nifedipine (0.77 +/- 0.23 ng/ml). Digoxin clearance was 2.2 +/- 0.6 and 2.7 +/- 0.8 ml/kg/min on placebo and 2.5 +/- 0.6 ml/kg/min on nifedipine. No change in pharmacologic effect of digoxin by nifedipine was observed, but mean blood pressure was lower and heart rates were accelerated. These data indicate that oral nifedipine does not alter digoxin concentrations or decrease renal clearance in healthy subjects.     

Interaction of 3'-azido-3'-deoxythymidine with organic ion transport in rat renal basolateral membrane vesicles.

3'-Azido-3'-deoxythymidine (AZT), a nucleoside analog effective against the acquired immunodeficiency syndrome virus, is actively secreted by rat, rabbit and human kidney. The mechanism of AZT transport across the basolateral membrane was characterized by examining the effect of AZT on organic cation and organic anion transport systems in rat renal basolateral membrane vesicles (BLMV) by using a rapid filtration assay. The following prototypic substrates were used: N1-[3H]methylnicotinamide and [3H]tetraethylammonium (TEA) for organic cations and p-[3H]aminohippurate (PAH) for an organic anion. AZT was an effective inhibitor of PAH transport. The dose-response curves for AZT and probenecid, an organic anion inhibitor, revealed IC50 values of 225 and 15 microM, respectively. To clarify further the actions of AZT at the organic anion transporter, counterflow studies were performed. Preloading BLMV with AZT trans-stimulated the uptake of PAH. The specificity of transport was assessed by examining the effect of AZT on organic cation transport. AZT did not inhibit uptake of NMN or TEA (pHin = pHout = 7.5). However, AZT slightly inhibited uptake of TEA under optimized transport conditions (1 mM TEA load). We conclude that AZT transport in rat BLMV is mediated predominantly by the renal organic anion transport system which is consistent with the capability of an organic anion to reduce the renal clearance of AZT in vivo.     

Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects

A microdose study of metformin was conducted to investigate the predictability of drug-drug interactions at the therapeutic dose (ThD). Healthy subjects received a microdose (100 μg) or ThD (250 mg) of metformin orally, with or without a potent and competitive multidrug and toxin extrusion (MATE) inhibitor, pyrimethamine (50 mg, p.o.), in a crossover fashion. Pyrimethamine significantly reduced the renal clearance of metformin by 23 and 35% at the microdose and ThD, respectively. At ThD, but not at microdose, it caused significant increases in the maximum concentration (C(max)) and area under the plasma concentration-time curve (AUC) of metformin (142 and 139% of control values, respectively). Human canalicular membrane vesicles showed pyrimethamine-inhibitable metformin uptake. Pyrimethamine did not affect plasma lactate/pyruvate after ThD of metformin but significantly reduced the renal clearance of creatinine, thereby causing elevation of plasma creatinine level. This microdose study quantitatively predicted a drug-drug interaction involving the renal clearance of metformin at ThD by pyrimethamine. Pyrimethamine is a useful in vivo inhibitor of MATE proteins.     

Hepatic and intestinal blood flow following thermal injury

Because cardiac output decreases after burn injuries, investigators have assumed, based upon dye clearance techniques, that hepatic and intestinal blood flow are also decreased following these injuries. Blood flow to the liver, stomach, small intestine, and kidney was determined by the uptake of 201thallium and 125I-labeled fatty acid (para-125I-phenyl-3-methyl pentanoic acid) in a 20% body surface area scald injury that also included plasma volume replacement resuscitation. Uptake of these radioisotopes was determined 15 minutes, 18 hours, and 72 hours after injury. The uptake of the 201thallium and 125I-labeled fatty acid by the gastrointestinal tissues was not statistically different at any of the time periods after comparison of the injured and control (sham-treated) animals. 201Thallium uptake by the kidney was significantly diminished 15 minutes after the burn injury (P less than 0.01). Based on these blood flow measurement techniques, the data suggest that the 20% body surface area scald injury did not alter blood flow to the liver or gastrointestinal tract within the initial 72 hours after the burn injury even though a decrease in renal blood flow was easily detected. These results suggest that the dysfunction of the gastrointestinal system or hepatic system observed after an acute burn injury is not simply the result of hypovolemic shock, which reduces both renal and mesenteric blood flow. These gastrointestinal and hepatic alterations may be related to a factor or factors other than intestinal ischemia.     

Renal Adaptation to a Low Phosphate Diet in Rats: BLOCKADE BY ACTINOMYCIN D

The major renal adaptive changes in response to selective dietary phosphate restriction are a marked reduction in urinary excretion of phosphate and an increased urinary excretion of calcium; at the cellular level, there is selective increase in renal cortical brush border membrane phosphate uptake and increase in specific activity of alkaline phosphatase. In the present study we examined whether these functional and biochemical adaptive changes could be blocked by drugs known to inhibit protein synthesis.Administration of actinomycin D or cycloheximide to rats switched from a diet with normal phosphate content (0.7%) to a diet with low (0.07%) phosphate content either completely (actinomycin D) or partially (cycloheximide) prevented the expected decrease in urinary excretion of phosphate and increase in the urinary excretion of calcium. The specific activity of alkaline phosphatase measured in crude membrane fraction (washed 100,000 g pellet) from renal cortical homogenate in animals fed a low phosphate diet and treated with actinomycin D or with cycloheximide was significantly lower than in control animals also on a low phosphate diet receiving placebo; but there were no differences between treated and untreated animals in the activities of two other brush border enzymes, gamma-glutamyltransferase and leucine aminopeptidase. Actinomycin D administered to rats maintained on a normal phosphate diet throughout the course of the experiment caused an increase in the urinary excretion of phosphate on the last (6th) day of the experiment but did not change urinary excretion of calcium. In acute clearance experiments, infusion of actinomycin D to rats adapted to a low phosphate diet did not increase fractional excretion of phosphate.In separate experiments, using the same dietary protocol as above, brush border membrane fraction (vesicles) was prepared from renal cortex of rats sacrificed at the end of the experiment. In this preparation Na(+)-dependent (32)Pi and d-[(3)H]glucose uptake and activities of brush border enzymes membrane were determined. Brush border membrane vesicles prepared from rats fed a low phosphate diet showed significantly higher Na(+)-dependent (32)Pi uptake compared with rats fed a normal phosphate diet. This increase in (32)Pi uptake was completely prevented when rats on a low phosphate diet were simultaneously treated with actinomycin D. These differences were specific for (32)Pi transport as no differences were observed in d-[(3)H]glucose uptake among the three groups. There was a positive correlation (r = 0.82, P < 0.01) between (32)Pi uptake and specific activity of alkaline phosphatase measured in aliquots of the same brush border membranes, whereas no such correlation was observed with two other brush border membrane enzymes gamma-glutamyltransferase and leucine aminopeptidase.These observations show that actinomycin D prevents both the functional and cellular renal adaptive changes induced by a low phosphate diet. Taken together, these observations suggest that renal adaptation to a low phosphate diet could be prevented by inhibition of de novo protein synthesis.     

Transport of p-aminohippurate, tetraethylammonium and D-glucose in renal brush border membranes from rats with acute renal failure

Transport of D-glucose, p-aminohippurate and tetraethylammonium has been studied using renal brush border membrane vesicles isolated from rats with uranyl nitrate-induced acute renal failure (ARF). Initial rate and overshoot magnitude of Na+ gradient-dependent D-glucose uptake were decreased in brush border membrane vesicles from ARF rats compared with normal rats, although there was no significant difference on D-glucose uptake in the presence of equilibrated Na+ between normal and ARF rats. Uptake of p-aminohippurate by membrane vesicles from ARF rats did not differ from normal membrane vesicles. Uptake of tetraethylammonium with or without an H+ gradient was decreased in membrane vesicles from ARF rats compared with normal rats. Dissipation rate of H+ gradient across brush border membranes did not differ between both groups. In vitro incubation of normal brush border membrane vesicles with uranyl nitrate caused no alteration in any substrate transport. However, enzyme activities such as (Na+ + K+)-adenosine triphosphatase in renal cortical homogenate were inhibited markedly in the presence of uranyl nitrate. These results suggest that uranyl nitrate-induced ARF caused alterations in the transport properties of renal brush border membranes and that these transport dysfunctions were not due to the direct effect of uranyl nitrate, but could be secondarily induced after the impairment of the integrity for tubular cells.     

Effect of quinidine on the digoxin receptor in vitro.

To investigate the basis for a clinically important digitalis-quinidine interaction that is characterized by increases in serums digoxin concentrations when quinidine is administered to digoxin-treated patients, we have studied in vitro the interaction of quinidine with the digoxin receptor. Evidence has been obtained that quinidine is capable of decreasing the affinity for digoxin of cardiac glycoside receptor sites on purified Na,K-ATPase and on intact human erythrocyte membranes. As others have shown, quinidine is capable of inhibiting Na,K-ATPase activity, and evidence has been obtained in the current study that, while quinidine can reduce the affinity of the enzyme for digoxin, it is also capable of acting together with digoxin in inhibiting enzyme activity to a degree greater than the inhibitory effect of digoxin alone. The concentrations of digoxin and quinidine used in this study were considerably greater than their therapeutic serum concentrations. Nevertheless, these observations are consistent with the hypothesis that the increases in serum digoxin concentrations and the decreases in volumes of digoxin distribution observed clinically when quinidine is administered to digoxin-treated patients may reflect, at least in part, a decrease in the affinity of tissue receptors for digoxin. The possibility must also be considered that enhanced cardiac effects of digoxin may occur clinically as the result of an augmentation, by quinidine, of digoxin effects, which more than compensates for the modest reduction in digoxin binding.