Effects of treatment of cimetidine (CMT) on pharmacokinetic behaviors of chlopropamide (CPA), an oral hypoglycemic agent, were investigated in rabbits with the standard renal clearance method. The renal clearance ratio and the renal tubular secretion volume of CPA were found to be markedly decreased by the treatment of CMT. Furthermore, the results of experiments using renal cortical slices demonstrated that CMT of the cationic drug decreased the accumlation of CPA. Inhibition of uptake by 2, 4-dinitrophenol indicated an energy dependence. Probenecid, a competitor for the anion transport mechanism, moderately inhibited CPA uptake.These observations indicate that the treatment of CMT may depress the renal excretion of CPA by inhibiting the tubular secretion.
Effects of co-administration of cimetidine(CMT) on pharmacokinetic behaviors of chlorpropamide(CPA),an oral hypoglycemic agent,after intravenous injection,were investigated in rabbits.The co-administration of CMT enhanced the plasma concentration of CPA,and reduced the amount of cumulative urinary excretion of CPA after intravenous bolus injection.Furthermore,the co-administration of CMT was found to decrease the renal clearance of CPA significantly,but to have no effect on its extrarenal clearance.These clearly indicate that the interaction of CPA with CMT is generated during renal excretion.For the purpose of elucidating the cause,effects of CMT on plasma protein binding of CPA,glomerular filtration rate (GFR),renal tubular secretion of PSP,and urinary pH were investigated.Plasma protein binding of CPA,GFR,and urinary pH were unchanged with and without CMT.But urinary excretion of PSP was decreased by co-administration of CMT.These observations suggest that the co-administration of CMT may depress the renal excretion of CPA by inhibiting the tubular secretion.
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