Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide.

AIMS: The aim of this open-label, placebo-controlled, randomized, four-period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide. METHODS: Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 microg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1-2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three-lead electrocardiograms. RESULTS: Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose-dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration-time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide-induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml-1 increase in plasma dofetilide concentration produced a 17-19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment-related adverse events or laboratory abnormalities. CONCLUSIONS: These results suggest that cimetidine increased dofetilide exposure by inhibiting renal tubular dofetilide secretion, whereas ranitidine did not. This effect is not an H2-receptor antagonist class effect but is specific to cimetidine. If therapy with an H2-receptor antagonist is required, it is recommended that cimetidine at all doses be avoided; since ranitidine has no effect on dofetilide pharmacokinetics or prolongation of the QTc interval, it can be seen as a suitable alternative.

Formation and pharmacokinetics of the active drug candoxatrilat in mouse, rat, rabbit, dog and man following administration of the prodrug candoxatril.

1. Candoxatrilat, an active neutral endopeptidase inhibitor, was released rapidly from the inactive prodrug candoxatril in vivo in mouse, rat, rabbit, dog and man. 2. Oral doses of [14C]-candoxatril were cleared rapidly, mostly by ester hydrolysis to candoxatrilat, in mouse, dog and man. A complementary intravenous study in man with [14C]-candoxatrilat showed that the active drug was virtually completely renally cleared. Neither candoxatril nor candoxatrilat underwent chiral inversion in man. 3. Systemic availability of candoxatrilat from the oral prodrug was estimated to be 88, 53, 42, 17 and 32% in mouse, rat, rabbit, dog and man respectively. Plasma clearance of candoxatril was too rapid to enable pharmacokinetic parameter calculation in mouse and rabbit; for man, the apparent oral clearance was 57.9 ml/min/kg and the elimination half-life was 0.46 h. 4. For intravenous candoxatrilat, total plasma clearance values were 32, 15, 5.5, 5.8 and 1.9 ml/min/kg for mouse, rat, rabbit, dog and man respectively. Renal clearance values were 8.7, 7.2, 2.9 and 1.7 ml/min/kg for mouse, rat, dog and man and these approximate to the respective glomerular filtration rates. Allometric scaling with respect to bodyweight across the species allowed reasonable prediction of the above two clearance parameters in man.

Effects of haemodialysis and continuous ambulatory peritoneal dialysis on abnormalities of ion transport in vivo in patients with chronic renal failure.

1. We have studied Na+/K+ pump activity in vivo in three groups of subjects: patients with chronic renal failure not receiving maintenance dialysis, patients being treated by either haemodialysis or continuous ambulatory peritoneal dialysis, and matched control subjects. 2. To do this we have measured the changes in plasma and intraerythrocytic rubidium concentrations after an oral load of rubidium chloride, having previously shown that changes in the disposition of rubidium measured in this way reflect changes in the activity of the Na+/K+ pump in vivo. 3. Erythrocyte rubidium uptake was significantly reduced both in ten patients with chronic renal failure not receiving maintenance dialysis and in 12 patients being treated by haemodialysis, when compared with 31 healthy control subjects. In contrast, erythrocyte rubidium uptake was not altered in 13 patients treated by continuous ambulatory peritoneal dialysis. There was also a significantly reduced rate constant for erythrocyte rubidium uptake in patients with undialysed chronic renal failure (0.66 h-1) and in those treated by haemodialysis (0.78 h-1), whereas in patients treated by continuous ambulatory peritoneal dialysis the rate constant for erythrocyte rubidium uptake was not significantly different from control values (1.36 h-1 and 1.41 h-1, respectively). 4. These findings are consistent with a reversal of the inhibition of erythrocyte Na+/K+ pump activity in vivo found in chronic renal failure by continuous ambulatory peritoneal dialysis, but not by haemodialysis. This difference may be due to the failure of haemodialysis to clear a circulating inhibitor of Na+, K(+)-ATPase or to the rapid re-accumulation of such an inhibitor after haemodialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for an altered mode of action of the sodium-lithium countertransporter in vivo in patients with untreated essential hypertension.

OBJECTIVE: To study the activity of the sodium-lithium (Na(+)-Li+) countertransport system in vivo in the erythrocytes of patients with untreated essential hypertension. DESIGN: Lithium substitutes for sodium efflux in the sodium-sodium (Na(+)-Na+) countertransport system. In essential hypertension the efflux of lithium from cells in vitro has been used as a measure of the activity of the Na(+)-Na+ countertransporter and has been shown to be increased. We administered oral lithium and used its disposition in erythrocytes to measure Na(+)-Li+ countertransporter activity in vivo. PATIENTS: Ten men with essential hypertension who had never taken any antihypertensive treatment were matched with 10 male controls for age, weight, and plasma and erythrocyte sodium and potassium concentrations. METHODS: Repeated measurements were made of plasma and intra-erythrocytic lithium concentrations during the 48h after the oral administration of 16.2 mmol lithium carbonate. Data were analysed using standard pharmacokinetic techniques. RESULTS: The rate of lithium efflux from the erythrocytes was increased in all patients with hypertension and in none of the normotensive controls. Hill plots derived from in vivo activation curves for erythrocytic Na(+)-Li+ countertransport showed that the normotensive participants had a Hill slope of 1 (SD 0.1), whereas the hypertensives had a Hill slope of 3.2 (SD 1.0). CONCLUSIONS: The activity of the Na(+)-L+ countertransport system is increased in untreated essential hypertension in vivo; this confirms in vitro findings. A new finding is that there is a change in either the stoichiometry or the co-operativity of lithium efflux via the Na(+)-L+ countertransport system, suggesting that the rate of sodium efflux may be greater than that of influx in the cells of people with hypertension.

Increases in Na/K pump numbers in isolated human lymphocytes exposed to lithium in vitro. Reversal by myo-inositol and by inhibitors of protein kinase C and the Na/H antiport.

Lithium (1-8 mM) caused a dose-dependent increase in the number of [3H]ouabain binding sites and in sodium/potassium (Na/K) pump activity in normal lymphocytes after incubation for 72 h. The increase in Na/K pump activity was due to an increase in the Vmax of the pump, with no change in the apparent affinity (Km) for potassium (rubidium). There was no change in the turnover number of the pump and the intracellular sodium concentration fell. The increase in [3H]ouabain binding sites was prevented by the addition of myo-inositol (10 mM), by inhibition of the protein kinase C with staurosporine (100 nM) and by inhibition of the Na/H antiport with dimethylamiloride (50 microM). These results suggest that the increase in Na/K pump activity caused by lithium is due to an increase in pump numbers and not due to increased activity of individual pumps or to an alteration in the affinity of the pumps for potassium. The increase in Na/K pump numbers and activity in lymphocytes exposed to lithium for 72 h may be related to altered Na/H antiport activity secondary to inhibition of phosphoinositol breakdown by lithium.

The effect of oral salbutamol on cation transport measured in vivo in healthy volunteers.

1. We have measured the effect of oral salbutamol on cation transport in vivo by studying the disposition of an oral load of rubidium chloride in healthy treated volunteers and in untreated matched controls. 2. During the administration of salbutamol there was a significantly lower plasma rubidium concentration 5 h after the administration of the oral load of rubidium chloride, reflecting an increase in the net clearance of rubidium from the plasma into at least some tissues in vivo. 3. There was no difference in either intraerythrocytic rubidium concentrations or the pseudo-rate constant for erythrocyte rubidium uptake in vivo after salbutamol. 4. Ex vivo incubation of whole blood preloaded in vivo with rubidium showed that the clearance of rubidium from the plasma was inhibited by 95% in the presence of the Na+,K(+)-ATPase inhibitor digoxin. 5. These data suggest that salbutamol stimulates cation transport via Na+,K(+)-ATPase in vivo into some tissues but not into the erythrocyte. 6. This pattern of change in rubidium disposition after salbutamol is completely different from the patterns of change we have seen in patients with essential hypertension or acute manic illness. We therefore suggest that the changes in erythrocyte rubidium uptake which we have previously described in vivo in patients with essential hypertension or acute manic illness do not result from beta 2-adrenoceptor-mediated catecholamine stimulation of Na+,K(+)-ATPase.