Pharmacokinetics and drug interactions of organic bases : ranitidine and ethambutol

Studies were conducted to characterize the pharmacokinetic parameters of ranitidine, an Hg-recePtor antagonist, in two animal species, rats and dogs to examine which species would be an appropriate animal model for man. The effect of renal insufficiency on ranitidine disposition was also studied in bilaterally nephrectomized animals. The pharmacokinetics of ethambutol (a chemotherapeutic agent) was also investigated in bilaterally nephrectomized dogs and in patients with varying degrees of renal impairment to provide data for dosage adjustment of ethambutol in renalIy impaired patients. The effect of steady-state concentrations of ethambutol and quinidine, an anti-arrhythmic organic base, on the disposition of ranitidine in rats was studied to identify any potential interaction when these basic drugs are co-administered. After intravenous administration of ranitidine in rats, both the plasma profile and biliary excretion rate showed a biexponential decline with similar half-lives (108.2 vs 95.9 min). The mean total clearance of ranitidine in rats was 30.8 ml/min/kg and the renal excretion and biliary excretion averaged 28.7[percent] and 5.0[percent], respectively. In comparison to rats, dogs excreted more ranitidine as unchanged drug (58.8[percent]). In dogs, ranitidine total body clearance averaged 6.1 ml/min/kg with terminal elimination half-life of 122.5 min. A distinct change in distribution and elimination of ranitidine was observed in bilaterally nephrectomized animals. A significant decrease (p <0.001) in total clearance was observed in rats (54[percent]) and in dogs (67[percent]) after nephrectomy. Nephrectomization resulted in a significant (p <0.001) decrease in the volume of distribution (Vdss) of ranitidine in rats decreasing from 3.6 1/kg to 2.5 1/kg. No change in the volume of distribution was observed in dogs. However Vdg was significantly reduced rats after nephrectomy with no change in dogs. Protein binding of ranitidine averaged <20[percent] in both species studied. Pharmacokinetic parameters of ranitidine observed in dogs appear to more closely resemble corresponding parameters reported in humans. The half-life of ranitidine was prolonged by 30[percent] (p <0.001) in ethambutol treated rats and 62[percent] (p <0.001) in quinidine treated rats, when compared to their respective controls. Total clearance decreased by 45[percent] (p <0.001) in ethambutol treated rats and 50[percent] in quinidine treated rats (p <0.001), with very little or no change in the volume of distribution. These results indicated a potential drug interaction due to competition for renal tubular secretion when these drugs are co-admini-stered clinically. In nephrectomized dogs, the total clearance of ethamtol was decreased by 36[percent] resulting in a 21[percent] prolongation of half-life with no change in Vdss- However, Vdg values showed a more pronounced change in all experiments. In patients with impaired renal function, creatinine clearance and serum creatinine values appeared to correlate well with the terminal elimination rate constant. Based on these relationships, it is recommended that the dose of ethambutol in total renal failure be approximately 7 mg/kg and in patients with 50[percent] renal impairment the administered dose should be approximately 11 mg/kg.