Renal impairment can alter the fraction of a drug dose absorbed, protein binding, renal drug clearance, and hepatic drug clearance. These changes can alter the steady-state plasma concentration of the drug (See Physiology of renal clearance of drugs).
Effect of renal impairment on fraction of drug absorbed (F)
There are reports that renal disease may reduce oral absorption because of alteration of gastric pH, edema of the gastrointestinal tract due to irritant properties of waste products such as urea, and administration of antacids.29 However, bioavailability studies typically compare area under the plasma concentration versus time (AUC) of drug given for healthy persons and renally impaired patients. AUC is determined by fraction of drug absorbed, drug clearance, and drug protein binding. Since clearance and protein binding can be affected by renal impairment, simple measurements of AUC for determination of F may be invalidated because of alterations in one or both of these factors.29 Techniques that correct for changes in clearance and protein binding have produced variable results when applied to studies of F in patients with renal impairment.29
Effect of renal impairment on drug protein binding
The plasma protein binding of acidic drugs (e.g., phenytoin, valproic acid) is markedly reduced in patients with severe renal impairment.35 The effects of lesser degrees of renal impairment have not been studied as extensively.
The proposed mechanisms for reduced protein binding in renal insufficiency include:29,35,36
- decreased plasma albumin concentration
- accumulation of endogenous binding inhibitors
- competition for binding sites by metabolites of the administered parent drug
For drugs cleared principally by hepatic enzymes, the complicated equation shown at the end of Physiology of renal clearance of drugs can be simplified to:
Thus, the total (protein-bound and nonbound) mean steady-state plasma concentration decreases when the free fraction of drug increases in situations such as renal insufficiency.
The mean steady-state free or non-protein bound concentration of drug (CssF) can be expressed as:
Combining the two equations above yields:
Note this important relationship: For drugs metabolized by hepatic enzymes, changes in protein binding affect the total steady-state plasma concentration, but the free drug plasma concentration remains constant.
For example, with renal insufficiency, the total plasma concentration of a protein-bound drug cleared by the liver, such as phenytoin, decreases owing to an increase in the free fraction of the drug, but the free concentration of phenytoin remains unchanged.37 Seizure patients with renal insufficiency may receive toxic doses of phenytoin if the total plasma concentration is the basis for selecting the dosing rate.
Another example of the effects of changes in protein binding on free and total drug plasma concentration is the interaction of valproate with phenytoin. Both drugs have high protein binding. When valproate is added to phenytoin, the free fraction of phenytoin increases because it is displaced from protein binding sites by valproate. The total phenytoin plasma concentration decreases, but the free phenytoin plasma concentration remains constant.38 This can lead to toxic dosing of phenytoin if the dosing rate is based on its total plasma concentration.
Effect of renal impairment on drug metabolism
Renal impairment will decrease the excretion of drugs eliminated by renal clearance (see next section). Certain drugs (e.g., acetaminophen) are metabolized by the kidney, and this metabolism is reduced in renal failure.29 No antiepileptic drugs (AEDs) are in this group. There is animal and human evidence that the nonrenal clearance of certain drugs is decreased by 20% to 80% in the presence of renal insufficiency.29
Metabolic enzyme systems that may be affected by renal impairment are:29
- hydroxylation
- O-demethylation
- N-demethylation
- glucuronidation
- deacetylation
- sulfoxidation
The mechanism of these metabolic changes may be accumulation of inhibitors or toxins or collateral effects of the disease causing renal insufficiency.
Hydroxylation, demethylation and glucuronidation are results of metabolism of some AEDs. This raises the possibility of a decrease in nonrenal clearance of some AEDs in renal failure. This possibility has not been studied extensively.
Effect of renal impairment on drug excretion:
Renal clearance can be defined asThe total clearance of the drug is the sum of renal clearance (CLr) plus hepatic clearance (CLH) plus other routes of clearance (e.g. sweat).
The effect of renal disease on drug clearance thus depends upon several factors:Where CLF= clearance via filtration, RS= the rate of renal tubular secretion, RR= the rate of renal tubular resorption, and Cp= drug plasma concentration.
- the relative contribution of renal clearance to total clearance
- drug filtration
- tubular secretion rate
- tubular resorption rate
- drug plasma concentration
For some drugs (e.g., gabapentin, levetiracetam), renal clearance accounts for most or all of total clearance.40 For other drugs (e.g., phenytoin, carbamazepine), renal clearance accounts for little of total clearance.
In renal impairment, the glomerular filtration rate (GFR) will decrease and the free fraction of drug in plasma may increase, as discussed above.The rate of filtration of a drug (Rf) depends on GFR, drug plasma concentration, and free fraction of the drug in plasma
Renal tubular secretion does not occur with the commonly used AEDs.
Tubular resorption depends upon lipid solubility and the ability to cross biological membranes. Lipid-soluble drugs readily cross the renal tubule and are readily resorbed. For example, phenytoin is highly lipid-soluble, and almost no phenytoin is cleared by the kidney.39
Thus, there can be no general statement about how renal impairment will affect total drug clearance, since the effect of renal impairment depends upon the combined effects of the factors listed above. The effects of renal impairment on specific AEDs are discussed separately.
Adapted from: Browne TR. Renal disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;49-62. With permission from Elsevier (www.elsevier.com).
