Annie Arvidsson

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 < 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.

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

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 < 0.01). The biliary clearance of digoxin decreased by 43%, from 187 ± 89 to 101 ± 55 ml/min (p < 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.

Quinidine reduces biliary clearance of digoxin in man.

Abstract. 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 < 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.

Influence of the Glomerular Filtration Rate on Renal Clearance of Ceftazidime in Cystic Fibrosis

SummaryThe renal handling of ceftazidime was studied in 8 patients with cystic fibrosis and 10 healthy controls. The renal clearance of ceftazidime (CLRcz) was measured after an intravenous single dose and during low and high plasma concentration steady-state infusions. The glomerular filtration rate (GFR) was simultaneously estimated by inulin clearance (CLinul). The average CLRcz (mean ± SD) was higher in cystic fibrosis patients (125 ± 20 ml/min/1.73m2) than in healthy controls (100 ± 9 ml/min/1.73m2) [p < 0.005]. Also CLinul (mean ± SD) was increased in cystic fibrosis patients (132 ± 30 ml/min/1.73m2) compared with healthy controls (103 ± 8 ml/min/1.73m2) [p < 0.02]. The mean renal clearance ratios of ceftazidime to inulin were close to unity after both the single dose and low and high dose steady-state infusions both in cystic fibrosis patients and in controls.These findings suggest that the glomerular filtration rate is the principal determinant of the elimination rate of ceftazidime. However, in all cystic fibrosis patients with a CLinul exceeding 125 ml/min/1.73m2 the clearance ratio was below unity, indicating tubular reabsorption of ceftazidime occurs in these individuals. The results demonstrate a higher but also more variable GFR in cystic fibrosis patients (74 to 174 ml/min/1.73m2), resulting in increased and accordingly variable ability to eliminate ceftazidime in cystic fibrosis. However, these pharmacokinetic changes are not large enough to call for special dosage considerations for ceftazidime in cystic fibrosis.

Renal excretion of cephapirin and cephaloridine: evidence for saturable tubular reabsorption.

Drug concentrations in plasma and urine were determined in 5 healthy subjects after intravenous infusion of 1 gm cephapirin and cephaloridine. Sampling of blood and urine was frequent and prolonged. Specimens were analyzed by high‐pressure liquid chromatography (HPLC). Renal clearance of cephapirin decreased to less than 5% of control in all subjects when drug concentrations in plasma and urine declined. Cephaloridine clearance decreased to a lesser extent. Our findings suggest that, besides tubular secretion and glomerular filtration, a saturable and probably active tubular reabsorption is also involved in the renal handling of these two cephalosporins. The saturable reabsorption process was characterized by its Michaelis‐Menten constant Km and its maximum transport capacity Tm.

Interindividual variability in biliary excretion of ceftriaxone: effects on biliary lipid metabolism and on intestinal microflora

Abstract. Ceftriaxone is a broad spectrum parenteral cephalosporin that is eliminated through renal as well as biliary excretion. In order to characterize factors influencing the biliary excretion of ceftriaxone, and possible effects of this organic anion on biliary lipid transport, we studied six healthy volunteers before and during ceftriaxone infusion. The biliary secretion rates of cholesterol, bile acids, phospholipids and ceftriaxone were determined using a duodenal perfusion technique, and the biliary lipid composition and cholesterol saturation of stimulated hepatic bile were determined. Changes in the intestinal microflora induced by ceftriaxone treatment were also analysed. There was a three‐fold interindividual variation in biliary excretion of ceftriaxone, and this was correlated with the secretion rate of bile acids (rs=0·83, P=0·05). During ceftriaxone infusion, the secretion rate of cholesterol was reduced by 32% (P<0·05), which resulted in a reduction of cholesterol saturation of bile, from 107±11 to 75±12% (SEM, P<0·05). The suppression of intestinal Escherichia coli and Bacteroides, and the proliferation of enterococci and lactobacilli were related to the biliary excretion of ceftriaxone. We conclude (i) that biliary excretion of ceftriaxone is of major importance for its effects on intestinal microflora, (ii) that secretion of this organic anion into bile is largely dependent on bile acid secretion, and (iii) that ceftriaxone inhibits the biliary secretion of cholesterol.

Increased Renal Clearance of Cefsulodin Due to Higher Glomerular Filtration Rate in Cystic Fibrosis

SummaryThe steady-state renal clearance of cefsulodin was studied in 6 patients with cystic fibrosis and 8 healthy controls. The drug was administered by constant rate infusion to obtain 2 values of plasma concentration, 2 and 30 mg/L. As an estimate of the glomerular filtration rate, the renal clearance of inulin was measured simultaneously.The results showed the figures for inulin clearance to be approximately 30% higher in cystic fibrosis patients than in healthy controls at both concentrations, and a corresponding increase in the renal clearance of cefsulodin was seen in patients over controls. The ratio between the renal clearances of the 2 substances was on average 0.9 in both groups.The correlation found between the 2 renal clearances (r = 0.75; p < 0.001) indicates that glomerular filtration rate has considerable influence on the renal elimination of cefsulodin. This finding emphasises the importance of glomerular filtration rate for the renal clearance of drugs in cystic fibrosis.

Digoxin-interactions in man: Spironolactone reduces renal but not biliary digoxin clearance

SummaryThe possibility of an inhibitory effect of spironolactone on the biliary clearance of digoxin has been investigated in 6 healthy subjects.Plasma clearance and the renal and biliary clearance of digoxin were determined twice at steady state (digoxin 0.5 to 1 mg·d−1 p.o. for 6 days), alone or in combination with spironolactone 200 mg daily, after an intravenous dose of digoxin (0.7 × oral dose) on Day 7. Plasma and urine were collected for 48 h. Biliary clearance of digoxin was determined on Day 8 by a duodenal perfusion technique.During spironolactone treatment plasma digoxin clearance tended to be lower (255 vs 224 ml/min; P=0.057) and renal clearance significantly lower (166 vs 144 ml/min), while the biliary clearance of digoxin remained unchanged (106 vs 103 ml/min).Thus, spironolactone reduced the renal clearance of digoxin by an average of 13%, without affecting its biliary clearance.