Principles of Drug Therapy in Patients With Decreased Kidney Function

Drug Absorption

There is little quantitative information about the influence of decreased kidney function in CKD patients on drug absorption. Several variables, including changes in gastrointestinal transit time and gastric pH, edema of the gastrointestinal tract, vomiting and diarrhea, and concomitant administration of phosphate binders, have been associated with alterations in the absorption of some drugs, such as digoxin and many of the fluoroquinolone antibiotics. The fraction of a drug that reaches the systemic circulation after oral versus intravenous administration (termed absolute bioavailability ) is rarely altered in CKD patients. However, alterations in the peak concentration (C _max ) and in the time to which the peak concentration is attained (t _max ) have been noted for a few drugs, suggesting that the rate, but not the extent of absorption, is altered. Although the bioavailability of some drugs, such as furosemide or pindolol, is reported as being reduced, there are no consistent findings in patients with CKD to indicate that absorption is actually impaired. However, an increase in bioavailability resulting from a decrease in metabolism during the drug’s first pass through the gastrointestinal tract and liver has been noted for some β-blockers and dihydrocodeine.

Drug Distribution

The volume of distribution of many drugs is significantly altered in patients with advanced CKD ( Table 35.1 ), and changes in patients with oliguric AKI are also reported. These changes are predominantly the result of altered plasma protein or tissue binding or of volume expansion secondary to reduced kidney sodium and water excretion. The plasma protein binding of acidic drugs, such as warfarin and phenytoin, typically is decreased in patients with CKD because of decreased concentrations of albumin. Changes in the conformation of albumin-binding sites and accumulation of endogenous inhibitors of binding may also contribute to decreased protein binding. In addition, the high concentrations of some drug metabolites that accumulate in CKD patients may interfere with the protein binding of the parent compound. Regardless of the mechanism, decreased protein binding increases the free or unbound fraction of the drug. On the other hand, the plasma concentration of the principal binding protein for several basic drug compounds, α ₁ -acid glycoprotein, is increased in kidney transplant patients and in hemodialysis patients. For this reason, the unbound fraction of some basic drugs (e.g., quinidine) may be decreased, and, as a result, the volume of distribution in these patients is decreased.

The net effect of changes in protein binding is usually an alteration in the relationship between unbound and total drug concentrations, an effect frequently encountered with phenytoin. The increase in the unbound fraction often more than doubles, to values as high as 20% to 25% from the normal of 10%, which may result in increased hepatic clearance and decreased total concentrations of phenytoin. Although the unbound concentration therapeutic range is unchanged (1 to 2 µg/mL), the therapeutic range for total phenytoin concentration is reduced to 5 to 10 µg/mL (normal, 10 to 20 µg/mL) as GFR fails to account for the doubling of the unbound fraction. Therefore, the maintenance of therapeutic unbound concentrations of 1 to 2 µg/mL provides the best target for individualizing phenytoin therapy in patients with decreased kidney function.

Altered tissue binding may also affect the apparent volume of distribution of a drug. For example, the distribution volume of digoxin is reported as being reduced by 30% to 50% in patients with severe CKD. This may be the result of competitive inhibition by endogenous or exogenous digoxin-like immunoreactive substances that bind to and inhibit membrane adenosine triphosphatase (ATPase). The absolute amount of digoxin bound to the tissue digoxin receptor is reduced, and the resultant serum digoxin concentration observed after administration of any dose is greater than expected.

Therefore, in CKD patients, a normal total drug concentration may be associated with either serious adverse effects secondary to elevated unbound drug concentrations or subtherapeutic responses because of an increased plasma-to-tissue drug concentration ratio. Monitoring of unbound drug concentrations is suggested for drugs that have a narrow therapeutic range, those that are highly protein bound (>80%), and those with marked variability in the bound fraction (e.g., phenytoin, disopyramide).

Drug Metabolism and Transport

CL _NR of drugs includes all routes of drug elimination excluding kidney excretion. Several metabolic enzymes and active transporters collectively constitute the primary pathways of CL _NR . Alterations in the function of and interactions between them can significantly affect the pharmacokinetic disposition and corresponding patient exposure to drugs that are substrates of nonrenal pathways. The effect of CKD on the expression or function of many of these pathways has been characterized in experimental models of kidney disease. For example, in rat models of end-stage kidney disease, hepatic expression of several cytochrome P450 (CYP) enzymes, including CYP3A1 and CYP3A2 (equivalent to human CYP3A4), is decreased by as much as 85%. CYP2C11 and CYP3A2 activity is also significantly decreased, but CYP1A1 activity is unchanged. CYP functional expression is also decreased in the intestine; CYP1A1 and CYP3A2 are decreased up to 40% and 70%, respectively.

Several hepatic reductase enzymes are also affected by kidney disease. Gene and protein expression of carbonyl reductase-1, aldo-keto reductase-3, and 11β-hydroxysteroid dehydrogenase-1 is decreased by as much as 93% and 76%, respectively, in CKD rats. Hepatic expression of the conjugative enzymes N -acetyltransferases (NAT) is also decreased, while uridine diphosphate-glucuronosyltransferases (UGT) are unchanged. Similarly, functional expression of several intestinal and hepatic transporters is altered in experimental models of kidney disease. The expression and corresponding activities of the efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) are decreased by as much as 65% in the intestine, but the uptake transporter organic anion-transporting polypeptide (OATP) is not affected. Conversely, in the liver, protein expression of P-gp, MRP2, and OATP is increased, unchanged, and decreased, respectively.

In humans with kidney disease, the activities of CYPs and reductases appear to be minimally affected. CYP2D6-mediated clearance of drugs is generally decreased in parallel with kidney function. It was previously reported that CYP3A4 activity was decreased, but recent data indicate minimal impact of decreased kidney function on the pharmacokinetics of CYP3A4 drug substrates, but that OATP uptake activity is decreased. Thus, perceived changes in CYP3A4 activity were likely due to altered transporter activity, not an alteration in CYP activity. The reduction of CL _NR of several drugs that exhibit overlapping CYP and transporter substrate specificity in patients with CKD stages 4 or 5 supports this premise ( Table 35.2 ). To date, prediction of the effect of decreased kidney function on the metabolism and/or transport of a particular drug is difficult, and a general quantitative strategy to adjust dosage regimens for drugs that undergo extensive CL _NR has not yet been proposed. However, some qualitative insight may be gained if one knows which enzymes or transporters are involved in the clearance of the drug of interest and how those proteins are affected by a decrease in kidney function.

The effect of CKD on the CL _NR of a particular drug is difficult to predict, even for drugs within the same pharmacologic class. The reductions in CL _NR for CKD patients have frequently been noted to be proportional to the reductions in GFR. In the small number of studies that have evaluated CL _NR in critically ill patients with AKI, residual CL _NR was higher than in CKD patients with similar levels of CL _CR , whether measured or estimated by the Cockcroft-Gault equation. Because an AKI patient may have a higher CL _NR than a CKD patient, the resultant plasma ­concentrations will be lower than expected and possibly subtherapeutic if classic CKD-derived dosage guidelines are followed.