Drug disposition in renal failure

Disposition in the Body. Rapidly but incompletely absorbed after oral administration bioavailability about 65%. Up to 90% of an intravenous dose is excreted in the urine, mainly as unchanged drug with up to 14% of the dose as a glucuronide conjugate. 2-Amino-4-chloro-5-sulphamoylanthranilicacid has been reported as a metabolite in several studies, but in other cases it has not been detected and it has been suggested that it is an analytical artefact produced during acid extraction procedures. In normal subjects, about 6 to 18% of a dose is eliminated in the faeces after intravenous administration this may be increased to about 60% in renal failure. 

Disposition in the Body. Completely and fairly rapidly absorbed after oral administration. About 88% of a dose is excreted in the urine in 48 hours with about 50% as unchanged drug and 30% as xipamide-O-glucuronide free amine metabolites have also been detected. In normal subjects, only traces are excreted in the bile, but biliary excretion may be extensive in renal failure. 

The ultimate disposition of minoxidU depends primarily on hepatic metabolism and only slightly on renal excretion of unchanged drug. Because of this, pharmacological activity is not cumulative in patients with renal failure. 

Verbeeck, R.K. (1982) Glucuronidation and disposition of drug glucuronides in patients with renal failure. A review. Drug Metabolism and Disposition, 10, 87-89. 

Clinically overt nephrotoxicity is the result of the intrinsic capacity of a toxin to damage renal cells or tissue, the susceptibility of the patient, and changes in disposition of the toxin fhat result in increased delivery to the target organ or tissue. In this chapter we will examine the latter aspect of nephrotoxicity and will focus on (i) drug interactions that potentially lead to nephrotoxicity and (ii) changes in drug disposition induced by renal failure. 

In patients with heart failure, lidocaine s volume of distribution and total body clearance may both be decreased. Thus, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Thus, although steady-state concentrations may be achieved in 8-10 hours in normal patients and patients with heart failure, 24-36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition. 

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