A novel method to predict the elimination half-lives and the renal excretion mechanisms of cephalosprins.

Abstract

A novel method was proposed to predict the elimination half-lives of cephalosporins from plasma protein binding (unbound fraction, f) and fraction of the dose excreted into urine (f*) on the basis of the following 4 assumptions: the drug is only distributed to the extracellular fluid, the bound fraction of the drug in plasma is independent of the plasma drug concentration, the binding protein of the drug is albumin and the unbound drug in plasma is excreted by the glomerular filtration and the contribution of active secretion and reabsorption is negligible. The VSS [apparent vol. of distribution at steady-state] and t1/2.beta. [half lives] of MT-141, one of cephalosporins, in rabbits, dogs and healthy human subjects were well predicted, whereas, in rats, the prediction of the both values failed. The t1/2.beta. of various cephalosporins in healthy subjects were calculated from f and f*, in reasonably good agreement with the observed ones, except for some cephalosporins reported to be secreted actively in the renal tubules. Comparison of the calculated t1/2.beta. with the observed ones makes it possible to presume the renal excretion mechanism. This method will be applicable to other drugs which satisfy the above 4 assumptions.